Change in serial liver stiffness measurement by magnetic resonance elastography and outcomes in NAFLD.

BACKGROUND AND AIMS: The impact of disease progression in NAFLD on liver outcomes remains poorly understood. We aimed to investigate NAFLD progression using longitudinal liver stiffness measurements (LSM) by serial magnetic resonance elastography (MRE) and the association with liver outcomes. APPROACH AND RESULTS: All adult patients with NAFLD who underwent at least two serial MREs for clinical evaluation at Mayo Clinic, Rochester, between 2007 and 2019 were identified from the institutional database. Progression and regression were defined based on LSM change of 19% above or below 19% of initial LSM, respectively, based on Quantitative Imaging Biomarker Alliance consensus. The association between change in LSM and liver-related outcomes occurring after the last MRE was examined using time-to-event analysis. A total of 128 participants underwent serial MREs (53% female, median age 59 years). The median time between paired MREs was 3.4 (range 1-10.7) years. NAFLD progression (LSM = +0.61 kPa/year) was identified in 17 patients (13.3%). NAFLD regression (-0.40 kPa/year) occurred in 35 patients (27.3%). Stable LSM was noted in 76 participants (59.4%). In NAFLD without cirrhosis at baseline ( n = 75), cirrhosis development occurred in 14% of LSM progressors and 2.9% of non-progressors ( p = 0.059) over a median 2.7 years of follow-up from the last MRE. Among those with compensated cirrhosis at baseline MRE ( n = 29), decompensation or death occurred in 100% of LSM progressors and 19% of non-progressors ( p < 0.001) over a median 2.5 years of follow-up after the last MRE. CONCLUSIONS: Noninvasive monitoring of LSM by conventional MRE is a promising method of longitudinal NAFLD monitoring and risk estimation of liver-related outcomes in NAFLD.

Magnetic resonance elastography for prediction of long-term progression and outcome in chronic liver disease: A retrospective study.

BACKGROUND AND AIMS: Although magnetic resonance elastography (MRE) has been well-established for detecting and staging liver fibrosis, its prognostic role in determining outcomes of chronic liver disease (CLD) is mostly unknown. APPROACH AND RESULTS: This retrospective study consisted of 1269 subjects who underwent MRE between 2007 and 2009 and followed up until death or last known clinical encounter or end of study period. Charts were reviewed for cirrhosis development, decompensation, and transplant or death. The cohort was split into baseline noncirrhosis (group 1), compensated cirrhosis (group 2), and decompensated cirrhosis (group 3). Cox-regression analysis with age, sex, splenomegaly, CLD etiology, Child-Pugh Score (CPS), Fibrosis-4 Index (FIB-4) score, and Model for End-Stage Liver Disease (MELD)-adjusted HR for every 1-kPa increase in liver stiffness measurement (LSM) were used to assess the predictive performance of MRE on outcomes. Group 1 (n = 821) had baseline median LSM of 2.8 kPa, and cirrhosis developed in 72 (8.8%) subjects with an overall rate of about 1% cirrhosis/year. Baseline LSM predicted the future cirrhosis with multivariable adjusted HR of 2.38 (p < 0.0001) (concordance, 0.84). In group 2 (n = 277) with baseline median LSM of 5.7 kPa, 83 (30%) subjects developed decompensation. Baseline LSM predicted the future decompensation in cirrhosis with FIB-4 and MELD-adjusted HR of 1.22 (p < 0.0001) (concordance, 0.75). In group 3 (n = 171) with median baseline LSM of 6.8 kPa (5.2, 8.4), 113 (66%) subjects had either death or transplant. Baseline LSM predicted the future transplant or death with HR of 1.11 (p = 0.013) (concordance 0.53) but not in CPS and MELD-adjusted models (p = 0.08). CONCLUSION: MRE-based LSM is independently predictive of development of future cirrhosis and decompensation, and has predictive value in future transplant/death in patients with CLD.

Chronic Liver Disease in the Older Patient-Evaluation and Management.

PURPOSE OF REVIEW: As our population ages, the number of elderly patients with advanced chronic liver disease (ACLD) will increase. In this review we explore risk factors for liver injury, noninvasive assessment of liver disease, complications of cirrhosis, and management of frailty and sarcopenia in the older patient with ACLD. RECENT FINDINGS: Multiple guidelines regarding ACLD have been updated over the past few years. New cutoffs for FIB-4 and NAFLD (MASLD - Metabolic Dysfunction Associated Steatotic Liver Disease) fibrosis scores for elderly patients are being validated. Older patients with MASLD benefit from caloric restriction, exercise programs, and GLP-1 agonists. Patients with ACLD need to be screened for alcohol use disorder with modified scoring systems, and if positive, benefit from referral to chemical dependency programs. Carvedilol and diuretics may safely be used in the elderly for portal hypertension and ascites, respectively, with careful monitoring. Malnutrition, frailty, sarcopenia, and bone mineral disease are common in older patients with ACLD, and early intervention may improve outcomes. Early identification of ACLD in elderly patients allows us to manage risk factors for liver injury, screen for complications, and implement lifestyle and pharmacological therapy to reduce decompensation and death. Future studies may clarify the role of noninvasive imaging in assessing liver fibrosis in the elderly and optimal interventions for nutrition, frailty, sarcopenia, bone health in addition to reevaluation of antibiotic prophylaxis for liver conditions with rising antibiotic resistance.

Clinical course of non-alcoholic fatty liver disease and the implications for clinical trial design.

BACKGROUND & AIMS: The predicted risk and timeline to progression to liver-related outcomes in the population with NAFLD are not well-characterized. We aimed to examine the risk and time to progression to cirrhosis, hepatic decompensation and death in a contemporary population over a long follow-up period, to obtain information to guide endpoint selection and sample size calculations for clinical trials on NAFLD-related cirrhosis. METHODS: This is a retrospective study of prospectively collected data in a medical record linkage system, including all adults diagnosed with NAFLD between 1996-2016 by clinical, biochemical and radiological criteria in Olmsted County, Minnesota and followed until 2019. Liver-related outcomes and death were ascertained and validated by individual medical record review. Time and risk of progression from NAFLD to cirrhosis to decompensation and death were assessed using multistate modeling. RESULTS: A total of 5,123 individuals with NAFLD (median age 52 years, 53% women) were followed for a median of 6.4 (range 1-23) years. The risk of progression was as follows: from NAFLD to cirrhosis: 3% in 15 years; compensated cirrhosis to first decompensation: 33% in 4 years (8%/year); first decompensation to ≥2 decompensations: 48% in 2 years. Albumin, bilirubin, non-bleeding esophageal varices and diabetes were independent predictors of decompensation. Among the 575 deaths, 6% were liver related. Therapeutic trials in compensated cirrhosis would require enrolment of a minimum of 2,886 individuals followed for >2 years to detect at least a 15% relative decrease in liver-related endpoints. CONCLUSION: In this population-based cohort with 23 years of longitudinal follow-up, NAFLD was slowly progressive, with liver-related outcomes affecting only a small proportion of people. Large sample sizes and long follow-up are required to detect reductions in liver-related endpoints in clinical trials. LAY SUMMARY: For patients with compensated non-alcoholic steatohepatitis-related cirrhosis, the time spent in this state and the risk of progression to decompensation are not well-known in the population. We examined the clinical course of a large population-based cohort over 23 years of follow-up. We identified that adults with compensated cirrhosis spend a mean time of 4 years in this state and have a 10% per year risk of progression to decompensation or death. The risk of further progression is 3-fold higher in adults with cirrhosis and one decompensating event. These results are reflective of placebo arm risks in drug clinical trials and are essential in the estimation of adequate sample sizes.

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 by Magnetic Resonance Elastography Predicts Future Cirrhosis, Decompensation, and Death in NAFLD.

OBJECTIVES: Magnetic resonance elastography (MRE) is the most accurate method of liver stiffness measurement (LSM) in nonalcoholic fatty liver disease (NAFLD). We aimed to investigate the role of MRE in the prediction of hard outcomes in NAFLD. METHODS AND RESULTS: Adults with NAFLD who underwent MRE between 2007 and 2019 at Mayo Clinic, Rochester were identified. Cox regression analyses were used to explore the predictive role of baseline LSM for 1) development of cirrhosis in noncirrhotic NAFLD and 2) development of liver decompensation or death in those with compensated cirrhosis. A total of 829 NAFLD subjects (54% women, median age 58 years) were identified. Of 639 subjects without cirrhosis, 20 developed cirrhosis after a median follow-up of 4 years. Baseline LSM was predictive of future cirrhosis development: age-adjusted HR = 2.93 (95% CI, 1.86-4.62, p <.0001) per 1 kPa increment (C-statistic = 0.86). Baseline LSM by MRE can be used to guide timing of longitudinal noninvasive monitoring: 5, 3 and 1 years for LSM of 2, 3 and 4-5 kPa, respectively. Of 194 subjects with compensated cirrhosis, 81 developed decompensation or death after a median follow-up of 5 years. Baseline LSM was predictive of future decompensation or death: HR = 1.32 (95% CI, 1.13-1.56, p = .0007) per 1 kPa increment after adjusting for age, sex and MELD-Na. The 1-year probability of future decompensation or death in cirrhosis with baseline LSM of 5 kPa vs 8 kPa is 9% vs 20%, respectively. CONCLUSION: In NAFLD, LSM by MRE is a significant predictor of future development of cirrhosis. These data expand the role of MRE in clinical practice beyond the estimation of liver fibrosis and provide important evidence that improves individualized disease monitoring and patient counseling.

The Role of Magnetic Resonance Elastography in the Diagnosis of Noncirrhotic Portal Hypertension.

Portal hypertension (PH) is defined as abnormal elevation of portal venous pressure with cirrhosis accounting for 90% of cases and 10% of cases classified as noncirrhotic PH (NCPH).1,2 The differentiation of cirrhotic PH (CPH) from NCPH is difficult (Supplementary Figure 1), with recent research efforts focusing on noninvasive evidence of increased hepatic stiffness.3,4 Magnetic resonance elastography (MRE) is an established imaging technique in the assessment of hepatic stiffness, and is now the most efficacious, noninvasive method to assess for hepatic fibrosis.5-8 The aim of this study was to assess the ability of magnetic resonance imaging (MRI) and MRE to differentiate between CPH and NCPH.

Natural history of clinical outcomes and hepatic decompensation in metabolic dysfunction-associated steatotic liver disease.

BACKGROUND & AIMS: The natural progression of hepatic decompensation in metabolic dysfunction-associated steatotic liver disease (MASLD) is not well-characterised. We aimed to describe it by conducting a retrospective analysis. METHODS: This longitudinal, retrospective analysis of well-characterised MASLD cohorts followed for hepatic decompensation and death. The sequence of liver-related events was evaluated, and the median time between hepatic decompensation episodes and death versus. transplantation was measured. RESULTS: Of the 2016 patients identified, 220 (11%) developed at least one episode of hepatic decompensation during a median follow-up of 3.2 years. Ascites was the most common first liver-related event [153 (69.5%)], followed by hepatic encephalopathy (HE) [55 (25%)] and variceal haemorrhage (VH) [30 (13.6%)]. Eighteen out of the 220 (8.1%) patients had more than one liver-related event as their first hepatic decompensation. Among the patients who had the first episode, 87 (39.5%) had a second episode [44 (50.5%) HE, 31 (35.6%) ascites, and 12 (13.7%) VH]. Eighteen out of 220 (8.1%) had a third episode [10 (55.5%) HE, 6 (33.3%) VH, and 2 (11.1%) ascites]. Seventy-three out of 220 (33.1%) died, and 31 (14%) received liver transplantation. The median time from the first episode to the second was 0.7 years and 1.3 years from the second episode to the third. The median survival time from the first episode to death or transplantation was 2.0 years. CONCLUSION: The most common first liver-related event in MASLD patients is ascites. The median survival from the first hepatic decompensation to either death or transplantation is 2 years.

Type 2 diabetes, hepatic decompensation, and hepatocellular carcinoma in patients with non-alcoholic fatty liver disease: an individual participant-level data meta-analysis.

BACKGROUND: Data are scarce regarding the development of hepatic decompensation in patients with non-alcoholic fatty liver disease (NAFLD) with and without type 2 diabetes. We aimed to assess the risk of hepatic decompensation in people with NAFLD with and without type 2 diabetes. METHODS: We did a meta-analysis of individual participant-level data from six cohorts in the USA, Japan, and Turkey. Included participants had magnetic resonance elastography between Feb 27, 2007, and June 4, 2021. Eligible studies included those with liver fibrosis characterisation by magnetic resonance elastography, longitudinal assessment for hepatic decompensation and death, and included adult patients (aged ≥18 years) with NAFLD, for whom data were available regarding the presence of type 2 diabetes at baseline. The primary outcome was hepatic decompensation, defined as ascites, hepatic encephalopathy, or variceal bleeding. The secondary outcome was the development of hepatocellular carcinoma. We used competing risk regression using the Fine and Gray subdistribution hazard ratio (sHR) to compare the likelihood of hepatic decompensation in participants with and without type 2 diabetes. Death without hepatic decompensation was a competing event. FINDINGS: Data for 2016 participants (736 with type 2 diabetes; 1280 without type 2 diabetes) from six cohorts were included in this analysis. 1074 (53%) of 2016 participants were female with a mean age of 57·8 years (SD 14·2) years and BMI of 31·3 kg/m2 (SD 7·4). Among 1737 participants (602 with type 2 diabetes and 1135 without type 2 diabetes) with available longitudinal data, 105 participants developed hepatic decompensation over a median follow-up time of 2·8 years (IQR 1·4-5·5). Participants with type 2 diabetes had a significantly higher risk of hepatic decompensation at 1 year (3·37% [95% CI 2·10-5·11] vs 1·07% [0·57-1·86]), 3 years (7·49% [5·36-10·08] vs 2·92% [1·92-4·25]), and 5 years (13·85% [10·43-17·75] vs 3·95% [2·67-5·60]) than participants without type 2 diabetes (p<0·0001). After adjustment for multiple confounders (age, BMI, and race), type 2 diabetes (sHR 2·15 [95% CI 1·39-3·34]; p=0·0006) and glycated haemoglobin (1·31 [95% CI 1·10-1·55]; p=0·0019) were independent predictors of hepatic decompensation. The association between type 2 diabetes and hepatic decompensation remained consistent after adjustment for baseline liver stiffness determined by magnetic resonance elastography. Over a median follow-up of 2·9 years (IQR 1·4-5·7), 22 of 1802 participants analysed (18 of 639 with type 2 diabetes and four of 1163 without type 2 diabetes) developed incident hepatocellular carcinoma. The risk of incident hepatocellular carcinoma was higher in those with type 2 diabetes at 1 year (1·34% [95% CI 0·64-2·54] vs 0·09% [0·01-0·50], 3 years (2·44% [1·36-4·05] vs 0·21% [0·04-0·73]), and 5 years (3·68% [2·18-5·77] vs 0·44% [0·11-1·33]) than in those without type 2 diabetes (p<0·0001). Type 2 diabetes was an independent predictor of hepatocellular carcinoma development (sHR 5·34 [1·67-17·09]; p=0·0048). INTERPRETATION: Among people with NAFLD, the presence of type 2 diabetes is associated with a significantly higher risk of hepatic decompensation and hepatocellular carcinoma. FUNDING: National Institute of Diabetes and Digestive and Kidney Diseases.

Association between Visceral Adipose Tissue and Non-Alcoholic Steatohepatitis Histology in Patients with Known or Suspected Non-Alcoholic Fatty Liver Disease.

(1) Purpose: To determine the association between visceral adipose tissue (VAT) and proton density fat fraction (PDFF) with magnetic resonance imaging (MRI), and hepatic steatosis (HS), non-alcoholic steatohepatitis (NASH) and hepatic fibrosis (HF) in patients with known or suspected non-alcoholic fatty liver disease (NAFLD). (2) Methods: 135 subjects that had a liver biopsy performed within 3 months (bariatric cohort) or 1 month (NAFLD cohort) of an MRI exam formed the study group. VAT volume was quantified at L2-L3 level on opposed-phase images with signal intensity-based painting using a semi-quantitative software. Liver PDFF and pancreas PDFF were calculated on fat fraction maps. Liver volume (Lvol) and spleen volume (Svol) were also calculated using a semi-automated 3D volume tool available on PACS. A histological analysis was performed by an expert hepatopathologist blinded to imaging findings. (3) Results: The mean Lvol, Svol, liver PDFF, pancreas PDFF and VAT of the study population were 2492.2 mL, 381.6 mL, 13.2%, 12.7% and 120.6 mL, respectively. VAT showed moderate correlation with liver PDFF (r = 0.41, p < 0.001) and weak correlation with Lvol (r = 0.38, p < 0.001), Svol (r = 0.20, p = 0.025) and pancreas PDFF (rs = 0.29, p = 0.001). VAT, Lvol and liver PDFF were significantly higher in patients with HS (p < 0.001), NASH (p < 0.05) and HF (p < 0.05). VAT was also significantly higher in the presence of lobular inflammation (p = 0.019) and hepatocyte ballooning (p = 0.001). The cut-off VAT volumes for predicting HS, NASH and HF were 101.8 mL (AUC, 0.7), 111.8 mL (AUC, 0.64) and 111.6 mL (AUC, 0.66), respectively. (4) Conclusion: The MRI determined VAT can be used for predicting the presence of HS, NASH and HF in patients with known or suspected NAFLD.

The need for an antibiotic stewardship program in a hospital using a computerized pre-authorization system.

OBJECTIVES: Antimicrobial stewardship programs (ASPs) have an important role in the appropriate utilization of antibiotics. Some of the core strategies recommended for ASPs are pre-authorization and prospective audit and feedback. In Turkey, a unique nationwide antibiotic restriction program (NARP) has been in place since 2003. The aim of this study was to measure the effect of a prospective audit and feedback strategy system along with the NARP. METHODS: A prospective quasi-experimental study was designed and implemented between March and June 2017. A computerized pre-authorization system was used as an ASP strategy to approve the antibiotics. During the baseline period, patients with intravenous (IV) antibiotic use ≥72 h were monitored without intervention. In the second period, feedback and treatment recommendations were given to attending physicians in the case of IV antibiotic use ≥72 h. The modified criteria of Kunin et al. and Gyssens et al. were followed for appropriateness of prescribing. Days of therapy (DOT) and length of stay (LOS) were calculated and compared between the two study periods. RESULTS: A total of 866 antibiotic episodes among 519 patients were observed. A significant reduction in systemic antibiotic consumption was observed in the intervention period (575 vs. 349 DOT per 1000 patient-days; p < 0.001). On multivariate analysis, prospective audit and feedback (odds ratio 1.5, 95% confidence interval 1.09-2.04; p = 0.011) and pre-authorization of restricted antibiotics (odds ratio 1.7; 95% confidence interval 1.2-2.31; p = 0.002) were the predictors of appropriate antimicrobial use. Mean LOS was decreased by 2.9 days (p = 0.095). CONCLUSIONS: This study showed that the antimicrobial restriction program alone was effective, but the system should be supported by a tailored ASP, such as prospective audit and feedback.