Clinical profiles and mortality rates are similar for metabolic dysfunction-associated steatotic liver disease and non-alcoholic fatty liver disease.

BACKGROUND & AIMS: Recently, the term metabolic dysfunction-associated steatotic liver disease (MASLD) has replaced non-alcoholic fatty liver disease (NAFLD). Concern remains regarding whether the evidence generated under the NAFLD definition can be used for MASLD. We compared the clinical profile and outcomes of NAFLD to MASLD using tertiary care- and population-based data. METHODS: Comparison data were obtained from our NAFLD database and the National Health and Nutrition Examination Survey (NHANES III). Clinical profiles and non-invasive tests (enhanced liver fibrosis [ELF] score, fibrosis-4 index [FIB-4] and vibration-controlled transient elastography) were compared. Mortality data were obtained from NHANES-National Death Index. All-cause mortality was assessed by Cox proportional hazards regression models and cause-specific mortality by competing risk analysis. RESULTS: There were 6,429 patients in the NAFLD database (age: 54 ± 12 years, 42% male, BMI 35.4 ± 8.3, waist circumference 112 ± 17 cm, 52% type 2 diabetes). Average scores for ELF, FIB-4 and liver stiffness were 9.6 ± 1.2, 1.69 ± 1.24,14.0 ± 11.8 kPa, respectively; 99% met MASLD criteria; 95% met MASLD on BMI only. Predictive accuracy of ELF and FIB-4 were identical between MASLD and NAFLD. We included 12,519 eligible participants from NHANES (age 43.00 years, 47.38% male, 22.70% obese, 7.28% type 2 diabetes, 82.51% ≥1 cardiometabolic criteria). Among the NHANES study population, there was excellent concordance between MASLD and NAFLD diagnoses: Cohen's kappa coefficient: 0.968 (95% CI 0.962-0.973) with 5.29% of NAFLD cases not meeting MASLD criteria. After a median follow-up of 22.83 years, there were no mortality differences between MASLD and NAFLD diagnoses (p values ≥0.05). CONCLUSIONS: NAFLD and MASLD are similar except individuals with MASLD seem to be older with slightly higher mortality risk, likely owing to cardiometabolic risk factors. Clinical profiles and non-invasive test thresholds were also identical. These data provide evidence that NAFLD and MASLD terminologies can be used interchangeably. For the small proportion of patients with NAFLD who do not meet MASLD criteria, further consideration is needed. IMPACT AND IMPLICATIONS: In June 2023, new terminology (MASLD) was adopted to replace the term NAFLD as a means to better describe what the liver disease is rather than what it is not, as well as to potentially reduce stigma. Given that MASLD requires at least one cardiometabolic risk factor, questions were raised as to whether this change in the definition would nullify the similarities between NAFLD and MASLD and require new evidence to be generated for MASLD. We used our NAFLD database and a US population-based database to show that the vast majority of patients with NAFLD fulfill criteria for MASLD. Non-invasive tests performed similarly in both groups. Mortality risk was slightly higher in those with MASLD, which is attributed to the presence of cardiometabolic risks. These results provide evidence that data generated in the past three decades for NAFLD can be used interchangeably for MASLD.

The impact of hepatitis B and C positive serologies on the outcomes of non-hepatic solid organ transplantation in the United States.

Chronic viral hepatitis B (HBV) and C (HCV) infection could negatively affect outcomes of non-hepatic solid organ transplantations due to the risk of viral reactivation in the presence of immunosuppression. This study aimed to determine post-transplant outcomes in patients with HBV or HCV positivity receiving non-hepatic solid-state organ transplant. Data was collected from the Scientific Registry of Transplant Recipients (SRTR) 2006-2021 for patients (≥18) who received a lung, heart, or kidney single organ transplant in the U.S. Hepatitis C positivity (HCV+) was determined as positive HCV Ab and hepatitis B positivity (HBV+) as positive HBsAg. We included N = 30,872 lung, N = 36,990 heart and N = 280,162 kidney transplant recipients. The prevalence of HBV+ was 1.3% in lung, 1.5% in heart and 1.7% in kidney patients, HCV+ was 2.2%, 2.2% and 5.0%, respectively. Post-transplant survival of patients with vs. without HBV+ was similar in all solid organ transplants (all p > .05). Similarly, there was no difference in post-transplant survival between lung transplant recipients with vs. without anti-HCV (all p > .05). Heart transplant recipients with HCV+ had higher crude post-transplant mortality (all p < .01). Similarly, there was higher post-transplant mortality in kidney transplant recipients with HCV+ (1-year: 6% vs. 3%; 5-year: 21% vs. 13%; 10-year: 47% vs. 31%; all p < .0001). In multivariate analysis controlling for confounders, only the association of HCV+ with higher post-kidney transplant mortality remained significant: adjusted hazard ratio (aHR) (95% CI) = 1.16 (1.12-1.20), p < .0001. There was no association of viral hepatitis seropositivity with the risk of graft failure in all groups (p > .05). In most cases, the presence of HBV or HCV serologies is not associated with adverse post-transplant outcomes in non-hepatic solid organ transplants. However, kidney transplant recipients who are positive for HCV serology have an increased risk for post-transplant mortality.

Clinical and patient-reported outcomes in patients with chronic hepatitis B and C and non-alcoholic fatty liver disease from real-world practices in Saudi Arabia, Turkey and Egypt.

Patients with chronic liver disease (CLD) experience health-related quality of life (HRQoL) and patient-reported outcomes (PROs) impairments. We assessed and identified predictors of HRQoL and PROs in CLD patients from Saudi Arabia (SA), Turkey and Egypt. Patients enrolled in Global Liver Registry™ with chronic hepatitis B (CHB), chronic hepatitis C (CHC) and non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) were included. Clinical data and PRO questionnaires (FACIT-F, CLDQ and WPAI) were compared across countries. Linear regression identified PRO predictors. Of the 4014 included patients, 26.9% had CHB, 26.9% CHC and 46.1% NAFLD/NASH; 19.2% advanced fibrosis. Compared across countries, CHB patients were younger in Egypt (mean age [years] 41.2 ± 11.4 vs. 45.0 ± 10.3 SA, 46.1 ± 12.0 Turkey), most often employed in SA (64.8% vs. 53.2% Turkey) and had the lowest prevalence of obesity in Turkey (26.7% vs. 37.8% SA, 38.5% Egypt). In SA, CHB patients had lowest prevalence of fibrosis and comorbidities (all p < .01). There was a higher frequency of males with NAFLD/NASH in SA (70.0% vs. 49.6% Turkey, and 35.5% Egypt). Among NAFLD/NASH patients, CLDQ-NAFLD/NASH scores were highest in SA (mean total score: 5.3 ± 1.2 vs. 4.8 ± 1.2 Turkey, 4.1 ± 0.9 Egypt, p < .01). Independent predictors of worse PROs included younger age, female sex, advanced fibrosis, non-hepatic comorbidities and lack of regular exercise (all p < .05). Clinical presentation and PRO scores of CLD patients vary across SA, Turkey and Egypt. Impairment of HRQoL is associated with demographic factors, lack of regular exercise, advanced fibrosis and non-hepatic comorbidities.

Prion protein with a mutant N-terminal octarepeat region undergoes cobalamin-dependent assembly into high-molecular weight complexes.

The cellular prion protein (PrPC) has a C-terminal globular domain and a disordered N-terminal region encompassing five octarepeats (ORs). Encounters between Cu(II) ions and four OR sites produce interchangeable binding geometries; however, the significance of Cu(II) binding to ORs in different combinations is unclear. To understand the impact of specific binding geometries, OR variants were designed that interact with multiple or single Cu(II) ions in specific locked coordinations. Unexpectedly, we found that one mutant produced detergent-insoluble, protease-resistant species in cells in the absence of exposure to the infectious prion protein isoform, scrapie-associated prion protein (PrPSc). Formation of these assemblies, visible as puncta, was reversible and dependent upon medium formulation. Cobalamin (Cbl), a dietary cofactor containing a corrin ring that coordinates a Co3+ ion, was identified as a key medium component, and its effect was validated by reconstitution experiments. Although we failed to find evidence that Cbl interacts with Cu-binding OR regions, we instead noted interactions of Cbl with the PrPC C-terminal domain. We found that some interactions occurred at a binding site of planar tetrapyrrole compounds on the isolated globular domain, but others did not, and N-terminal sequences additionally had a marked effect on their presence and position. Our studies define a conditional effect of Cbl wherein a mutant OR region can act in cis to destabilize a globular domain with a wild type sequence. The unexpected intersection between the properties of PrPSc's disordered region, Cbl, and conformational remodeling events may have implications for understanding sporadic prion disease that does not involve exposure to PrPSc.

The Potential Role of Fatigue in Identifying Patients With NASH and Advanced Fibrosis Who Experience Disease Progression.

BACKGROUND AND AIMS: Fatigue is common in patients with advanced liver disease. We investigated fatigue and clinical outcomes among patients with advanced nonalcoholic steatohepatitis (NASH). METHODS: In this study, patients with biopsy confirmed NASH and bridging fibrosis (F3) or compensated cirrhosis (F4) were followed for up to 2 years. The Chronic Liver Disease Questionnaire for Nonalcoholic Steatohepatitis (CLDQ-NASH) fatigue domain at baseline (range, 1-7; lower score indicating worse fatigue) quantified fatigue. The Cox proportional hazards model was used to study time to liver-related clinical events (progression to histologic cirrhosis or hepatic decompensation in F3, hepatic decompensation in F4). RESULTS: Of the 1679 NASH patients with fibrosis, 802 had F3 and 877 had F4 (58 ± 9 years of age, 40% male, 74% type 2 diabetes). During median follow-up of 16 months (interquartile range, 14-18), 15% (n = 123) of NASH F3 patients experienced liver-related events and 3.5% (n = 31) of NASH F4 patients experienced hepatic decompensation. Mean baseline CLDQ-NASH fatigue score in F3 patients was 4.77 ± 1.36; NASH F3 patients who experienced liver-related events had lower baseline scores: 4.47 ± 1.36 vs 4.83 ± 1.35 (P = .0091). The mean fatigue score in F4 was 4.56 ± 1.44; these scores were lower in patients who decompensated in follow-up: 3.74 ± 1.31 vs 4.59 ± 1.43 (P = .0011). The association of lower fatigue scores and risk of liver-related or decompensation events was significant after adjustment for confounders (adjusted hazard ratio per 1 point in fatigue score in F3, 0.85; 95% confidence interval, 0.74-0.97; P = .02; adjusted hazard ratio in F4, 0.62; 95% confidence interval, 0.48-0.81; P = .0004). CONCLUSION: Worse fatigue at baseline is associated with a higher risk of adverse clinical events in patients with NASH-related advanced fibrosis and cirrhosis.

Clinical and patient-reported outcome profile of patients with hepatitis B viral infection from the Global Liver Registry™.

Chronic hepatitis B (CHB) infection is one of the most common causes of cirrhosis and liver cancer worldwide. Our aim was to assess clinical and patient-reported outcome (PRO) profile of CHB patients from different regions of the world using the Global Liver Registry. The CHB patients seen in real-world practices are being enrolled in the Global Liver Registry. Clinical and PRO (FACIT-F, CLDQ, WPAI) data were collected and compared to baseline data from CHB controls from clinical trials. The study included 1818 HBV subjects (48 ± 13 years, 58% male, 14% advanced fibrosis, 7% cirrhosis) from 15 countries in 6/7 Global Burden of Disease super-regions. The rates of advanced fibrosis varied (3-24%). The lowest PRO scores across multiple domains were in HBV subjects from the Middle East/North Africa (MENA), the highest - Southeast/East and South Asia. Subjects with advanced fibrosis had PRO impairment in 3 CLDQ domains, Activity of WPAI (p < 0.05). HBV subjects with superimposed fatty liver had more PRO impairments. In multivariate analysis adjusted for location, predictors of PRO impairment in CHB included female sex, advanced fibrosis, and non-hepatic comorbidities (p < 0.05). In comparison to Global Liver Registry patients, 242 controls from clinical trials had better PRO scores (Abdominal, Emotional, and Systemic scores of CLDQ, all domains of WPAI) (p < 0.05). In multivariate analysis with adjustment for location and clinicodemographic parameters, the associations of PROs with the enrollment setting (real-life Global Liver Registry vs. clinical trials) were no longer significant (all p > 0.10). The clinico-demographic portrait of CHB patients varies across regions of the world and enrollment settings. Advanced fibrosis and non-hepatic comorbidities are independently associated with PRO impairment in CHB patients.

Can Frequent Toothbrushing Reduce the Risk of Cirrhosis among Patients with Nonalcoholic Fatty Liver Disease? Hints from a Registry-Based Study.

INTRODUCTION: While poor oral hygiene has been previously associated with an increased risk of nonalcoholic fatty liver disease (NAFLD), its association with hepatic fibrosis remains unclear. Here, we sought to analyze if toothbrushing frequency, an easy-to-assess indicator of oral health habits, would be associated with liver stiffness measurement (LSM) by transient elastography (TE) in patients with an established diagnosis of NAFLD. METHODS: In this registry-based study, LSM was measured in 1,156 patients with NAFLD and analyzed in relation to the self-reported daily frequency of toothbrushing. LSM values ≥12 kPa were considered indicative of cirrhosis. RESULTS: A trend toward a stepwise decrease (cross-sectional p = 0.13) in LSM was found in patients who reported having their teeth brushed more frequently: less than once a day (10.6 ± 8.6 kPa; 13% of the study sample), once a day (9.95 ± 8.40 kPa; 40%), twice a day (9.21 ± 7.63 kPa; 43%), and after every meal (8.91 ± 5.30 kPa; 4%). Patients who brushed their teeth less than once a day had a significantly higher prevalence of LSM values ≥12 kPa (p < 0.05). In multivariable logistic regression analysis, the association of LSM values ≥12 kPa with toothbrushing habits remained statistically significant for less than once a day (odds ratio = 1.69, 95% confidence interval = 1.07-2.66, p = 0.02) with reference to twice a day or after every meal. CONCLUSION: Among patients with NAFLD, there is an independent association between brushing teeth less than once a day and TE-established cirrhosis.

Expediting Treatment of Trauma Patients in the Emergency Department: Rapid Trauma Evaluation (RTE).

BACKGROUND: Criteria for trauma determination evolves. We developed/evaluated a Rapid Trauma Evaluation (RTE) process for a trauma patient subset not meeting preestablished trauma criteria. METHODS: Retrospective study (July 2019 - May 2020) for patients either > 65 years with ground level fall within 24 hours or in a motorcycle collision (MCC) arriving by EMS not meeting ACS trauma-criteria. RTE process was immediate evaluation by nurse/EMT, room placement, physician notification, undressing/gowning, vital signs, head-to-toe assessment, upgrade trauma status. Number/type of admissions, discharges, trauma upgrades, LOS obtained via trauma-registry and chart-review. For comparison, historic controls (HC) were used [all patients meeting RTE criteria seen in the ED prior to RTE (Apr- June 2019)]. RESULTS: The RTE cohort (n=755) was 77% falls,23% MCCs, median age 82 [IQR 74-88] years; 42% male-Among falls, 3.2% required a modified-upgrade; 0.7% full-upgrade, 55% admitted [29.4% trauma). HC (n=575) was 92.3% falls, 7.7% MCCs, median age 81 (IQR: 67-88) years, 40.5% males-57.4% admitted (22% trauma). RTE MCC median age 42 (IQR:30-49) years, 84.4% male- 21.9% were upgraded [(6 modified-trauma; 1 full-trauma; 43.8% admitted (85.7% trauma)]. HC MCC median age 29 (IQR: 23-41) years, 95.5% male, 54.5% admitted (75% trauma]. No difference on demographics, admissions or discharges between groups (P>0.05) except HC MCC was younger (P<0.005). RTE median LOS was shorter than HC [203 (IQR: 147-278) minutes vs. 286 (IQR: 205-392) minutes, P<0.001]. CONCLUSIONS: Patients > 65 years with a ground level fall or in a MCC arriving via EMS not meeting ACS trauma criteria may benefit from RTE.

Neutralizing Monoclonal Antibody Treatment Reduces Hospitalization for Mild and Moderate Coronavirus Disease 2019 (COVID-19): A Real-World Experience.

BACKGROUND: Neutralizing monoclonal antibody (NmAb) treatments have received Emergency Use Authorization to treat patients with mild or moderate COVID-19 infection. To date, no real- world data on the efficacy of NmAbs have been reported from clinical practice. We assessed the impact of NmAb treatment given in the outpatient clinical practice setting on hospital utilization. METHODS: Electronic medical records were used to identify adult COVID-19 patients who received NmAbs (bamlanivimab [BAM] or casirivimab and imdevimab [REGN-COV2]) and historic COVID-19 controls. Post-index hospitalization rates were compared. RESULTS: 707 confirmed COVID-19 patients received NmAbs and 1709 historic COVID-19 controls were included; 553 (78%) received BAM, 154 (22%) received REGN-COV2. Patients receiving NmAb infusion had significantly lower hospitalization rates (5.8% vs 11.4%, P < .0001), shorter length of stay if hospitalized (mean, 5.2 vs 7.4 days; P = .02), and fewer ED visits within 30 days post-index (8.1% vs 12.3%, P = .003) than controls. Hospitalization-free survival was significantly longer in NmAb patients compared with controls (P < .0001). There was a trend towards a lower hospitalization rate among patients who received NmAbs within 2-4 days after symptom onset. In multivariate analysis, having received an NmAb transfusion was independently associated with a lower risk of hospitalization after adjustment for age, sex, race, BMI, and referral source (adjusted HR [95% CI], .54 [0.38-0.79]; P = .0012). Overall mortality was not different between the 2 groups. CONCLUSIONS: NmAb treatment reduced hospital utilization, especially when received within a few days of symptom onset. Further study is needed to validate these findings.

The Impact of NASH to Liver Transplantations With Hepatocellular Carcinoma in the United States.

Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease worldwide.1,2 It is believed that about one fourth of the world population may have NAFLD.3 The Global Burden of Disease data suggest that NAFLD and nonalcoholic steatohepatitis (NASH) are the main drivers of liver disease burden in most regions of the world, including that of hepatocellular carcinoma (HCC).4,5.

Hepatic Fat Reduction Due to Resmetirom in Patients With Nonalcoholic Steatohepatitis Is Associated With Improvement of Quality of Life.

BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH) is a chronic liver disease associated with adverse clinical outcomes and impaired health-related quality of life (HRQL). METHODS: Patients with biopsy-proven non-cirrhotic NASH with hepatic fat fraction of ≥10% by magnetic resonance imaging-proton density fat fraction were enrolled in a phase 2, multicenter, double-blind, randomized, placebo-controlled study of resmetirom. HRQL was assessed using Short Form-36 throughout 36 weeks of treatment. RESULTS: One hundred twenty-five NASH patients were enrolled (50 ± 11 years old, 50% male, 94% white, body mass index 35 ± 6 kg/m2, 39% with diabetes mellitus). Of these, 84 patients received 80 mg of resmetirom daily, and 41 received placebo. At baseline, HRQL scores were not different from general population norms (Physical Component Summary [PCS] 47.9 ± 9.3 vs 50, Mental Component Summary 50.4 ± 10.0 vs 50; all P > .05). By treatment week 12, patients who received resmetirom experienced improvement of Bodily Pain and Short Form-6D utility scores (P < .05); no HRQL improvement was noted in placebo (all P > .05). Improvement in PCS continued up to week 36 of treatment with resmetirom, again with no improvement in placebo group (all P > .05). Adjusted for the baseline score and clinicodemographic confounders, meeting the endpoint of a decrease in proton density fat fraction of ≥30% by week 12 (met by 54 of 116 treatment completers; 47 of 54 on resmetirom) was independently associated with greater improvements in Physical Functioning and PCS scores at week 36 (P < .05). Patients with improvement in NASH and fibrosis on liver biopsy also showed improvement in components of HRQL. CONCLUSIONS: Patients with NASH treated who improved their hepatic fat fraction and/or Nonalcoholic Fatty Liver Disease Activity Score on serial liver biopsy experienced improvement of HRQL. Further studies are needed to confirm long-term sustainability of that improvement. CLINICALTRIALS: gov #NCT02912260.

Serum Biomarkers are Associated With Atherosclerotic Cardiovascular Disease Among Patients With Nonalcoholic Fatty Liver Disease Undergoing Elective Angiography.

BACKGROUND & AIMS: Cardiovascular disease is the most common cause of death among patients with nonalcoholic fatty liver disease (NAFLD). We assessed select cardiac biomarker associations for existing or future coronary artery disease (CAD) risk in patients with NAFLD. METHODS: Patients with/without NAFLD undergoing elective cardiac angiography were prospectively enrolled. Severe CAD was defined as presence of at least 1 proximal artery >70% stenosis; risk of severe CAD as either existing severe CAD or atherosclerotic cardiovascular disease score ≥20; NAFLD was defined as hepatic fat in the absence of other liver diseases. Cardiac biomarkers (high-sensitivity C-reactive protein, N-terminal pro-brain natriuretic peptide, and high-sensitivity cardiac troponin I [hs-cTnI]) were measured using Atellica Solution assays (Siemens Healthineers). RESULTS: A total of 619 patients were enrolled (mean age, 63 ± 10 years; 80% male; 31% type 2 diabetes; 65% NAFLD); 42% had severe CAD, and 57% had risk of severe CAD. NAFLD prevalence was similar between patients with and without severe CAD (68% vs 62%; P > .05). Patients with NAFLD with severe CAD (44%) or with risk of severe CAD (58%) had higher levels of hs-cTnI than NAFLD controls (both P < .001). Presence of severe CAD or risk of severe CAD in all patients was associated with older age, male, aspects of metabolic syndrome, and elevated hs-cTnI: odds ratio 2.0 (95% confidence interval [CI],1.4-2.9) and 1.8 (95% CI, 1.1-3.0), respectively; 2.3 (95% CI, 1.4-3.8) and 2.2 (95% CI, 1.2-4.2), respectively, in patients with NAFLD (all P < .02). CONCLUSION: CAD is common in patients with NAFLD. High hs-cTnI was associated with an increased risk of CAD. Pending validation, hs-cTnI may be a useful marker for CAD risk prediction in patients with NAFLD.

The Association of Histologic and Noninvasive Tests With Adverse Clinical and Patient-Reported Outcomes in Patients With Advanced Fibrosis Due to Nonalcoholic Steatohepatitis.

BACKGROUND & AIM: Fibrosis is an independent predictor of death in nonalcoholic steatohepatitis (NASH). We assessed the associations between histologic and noninvasive tests (NITs) for fibrosis with clinical and patient-reported outcomes (PROs) in advanced NASH. METHODS: Patients with advanced NASH (NASH Clinical Research Network stage F3 or F4) were enrolled in 4 multinational clinical trials of simtuzumab and selonsertib. Liver biopsy samples, NIT results, and PROs (Short Form-36, Chronic Liver Disease Questionnaire-NASH, EuroQol-5D, and Work Productivity and Activity Impairment) were prospectively collected. RESULTS: A total of 2154 patients with advanced NASH were included: 52.5% with F4 NASH, 40% male, 72% with type 2 diabetes, baseline liver stiffness of 24.1 ± 14.2 kPa in F4 disease and 14.6 ± 8.0 kPa in F3 disease, baseline mean Enhanced Liver Fibrosis score of 11.4 ± 1.2 in F4 disease and 10.3 ± 1.0 in F3 disease, and a median follow-up of 16 months. Of those with baseline F3 disease, 16.7% experienced disease progression to cirrhosis, whereas for those with F4 disease, 7.3% experienced clinical events (39% ascites, 24% hepatic encephalopathy); patients who progressed had higher baseline NIT scores (all P < .0001). Adjusted for baseline levels, increases in NIT scores were also associated with increased risk of disease progression in both the F3 and F4 groups (P < .01 for all NITs in F3 and for ELF, NAFLD Fibrosis Score, Fibrosis-4 (FIB-4), and liver stiffness in F4). Higher NIT scores were found to be associated with impairment in PROs: ELF, ≥10.43; Nonalcoholic Fatty Liver Disease Fibrosis Score, ≥1.80; Fibrotest score, ≥0.54; liver stiffness, ≥23.4 kPa. During treatment, patients with decreases in NIT scores experienced improvement of their PRO scores, whereas those with increase in NIT scores had their PRO scores worsen (P < .05). CONCLUSIONS: Baseline NIT scores and their changes over time are predictors of adverse clinical and PROs in patients with advanced NASH. (ClinicalTrials.gov, Numbers NCT01672866, NCT01672879, NCT03053050, and NCT03053063).

Long-term Patient-Centered Outcomes in Cirrhotic Patients With Chronic Hepatitis C After Achieving Sustained Virologic Response.

BACKGROUND & AIMS: Achieving sustained virologic response (SVR) among patients with hepatitis C virus (HCV) leads to patient reported outcome (PRO) improvement. We aimed to assess the long-term post-SVR PRO trends in HCV patients with cirrhosis. METHODS: Patients with HCV and cirrhosis treated in clinical trials with direct acting antiviral agents (DAAs) who achieved SVR-12 were prospectively enrolled in a long-term registry (clinicaltrials.gov #NCT02292706). PROs were collected every 24 weeks using the Short Form-36v2 (SF-36), CLDQ-HCV, and WPAI-HCV. RESULTS: Pre-treatment baseline data were available for 854 cirrhotic patients who achieved SVR after DAAs. Of these, 730 had compensated (CC) and 124 had decompensated cirrhosis (DCC) before treatment- patients with DCC reported severe impairment in their PROs in comparison to CC patients (by mean -5% to -16% of a PRO range size; p < .05 for 16 out of 20 studied PROs]. After achieving SVR and registry enrollment, significant PRO improvements were noted from pre-treatment levels in 11/20 domains for those with DCC (+4% to +21%) and 19/20 PRO domains in patients with CC (+3% to +17%). Patients with baseline DCC had higher rates of hepatocellular carcinoma and mortality (P < .05). In patients with CC, the PRO gains persisted up to 168 weeks (3.5 years) of registry follow-up. In patients with DCC, the improvements lasted for at least 96 weeks but a declining trend after year 2. CONCLUSIONS: Patients with HCV cirrhosis experience severe PRO impairment at baseline with sustainable improvement after SVR. Though those with DCC experience improvement, there is a decline after 2 years.

Obeticholic Acid Impact on Quality of Life in Patients With Nonalcoholic Steatohepatitis: REGENERATE 18-Month Interim Analysis.

BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH) affects patients' health-related quality of life (HRQoL). Patient-reported outcomes (PROs) evaluating HRQoL were assessed in the RandomizEd Global Phase 3 Study to Evaluate the Impact on NASH with FibRosis of Obeticholic Acid TreatmEnt (REGENERATE) study, which showed that obeticholic acid (OCA) significantly improved fibrosis in patients with NASH. METHODS: Noncirrhotic NASH patients in a phase 3, double-blind, randomized, placebo-controlled, multicenter, international study of OCA were enrolled. The Chronic Liver Disease Questionnaire-NASH and EuroQol EQ-5D-5L were administered at baseline, 6, 12, and 18 months. RESULTS: There were 1218 patients (age, 54.1 ± 11.5 y; 57% women; 43% stage F3) in the expanded intent-to-treat population (stages, F1-F3) assigned randomly to 10 mg (N = 407) or 25 mg (N = 404) OCA or placebo (N = 407). Baseline measurements were balanced across treatment groups for EuroQol EQ-5D-5L and Chronic Liver Disease Questionnaire-NASH, including Itch score: 5.75 ± 1.53 (scale 1-7, with 7 representing no itching). Nineteen (1.6%) patients discontinued therapy (protocol mandated) because of grade 3 pruritus. Patients receiving 25 mg OCA experienced mild worsening of itch scores primarily in the first months of treatment: mean ± SE change from baseline -0.66 ± 0.12, -0.44 ± 0.12, and -0.42 ± 0.13 at 6, 12, and 18 months, respectively (all P < .01). No other PRO worsening was associated with 25 mg OCA. Patients experiencing fibrosis improvement, Nonalcoholic Fatty Liver Disease Activity Score decrease (by ≥2 points), or NASH resolution had greater PRO improvements in some domains. CONCLUSIONS: NASH patients evaluated in REGENERATE had impaired quality of life and underlying pruritus at baseline. Improvement of NASH corresponded with improvement in several HRQoL domains. Generally mild pruritus occurs early after OCA therapy initiation and does not worsen over time. CLINICALTRIALS: gov: NCT02548351.

A Global Survey of Physicians Knowledge About Nonalcoholic Fatty Liver Disease.

BACKGROUND & AIMS: Despite rapidly increasing nonalcoholic fatty liver disease (NAFLD) prevalence, providers' knowledge may be limited. We assessed NAFLD knowledge and associated factors among physicians of different specialties globally. METHODS: NAFLD knowledge surveys containing 54 and 59 questions covering 3 domains (epidemiology/pathogenesis, diagnostics, and treatment) were completed electronically by hepatologists, gastroenterologists (GEs), endocrinologists (ENDOs), and primary care physicians (PCPs) from 40 countries comprising 5 Global Burden of Disease super-regions. Over 24 months, 2202 surveys were completed (488 hepatologists, 758 GEs, 148 ENDOs, and 808 PCPs; 50% high-income Global Burden of Disease super-region, 27% from North Africa and Middle East, 12% Southeast Asia, and 5% South Asian and Latin America). RESULTS: Hepatologists saw the greatest number of NAFLD patients annually: median 150 (interquartile range, 60-300) vs 100 (interquartile range, 35-200) for GEs, 100 (interquartile range, 30-200) for ENDOs, and 10 (interquartile range, 4-50) for PCPs (all P < .0001). The primary sources of NAFLD knowledge acquisition for hepatologists were international conferences (33% vs 8%-26%) and practice guidelines for others (39%-44%). The Internet was the second most common source of NAFLD knowledge for PCPs (28%). NAFLD knowledge scores were higher for hepatologists than GEs: epidemiology, 62% vs 53%; diagnostics, 80% vs 73%; and treatment, 61% vs 58% (P < .0001), and ENDOs scores were higher than PCPs: epidemiology, 70% vs 60%; diagnostics, 71% vs 64%; and treatment, 79% vs 68% (P < .0001). Being a hepatologist or ENDO was associated with higher knowledge scores than a GE or PCP, respectively (P < .05). Higher NAFLD knowledge scores were associated independently with a greater number of NAFLD patients seen (P < .05). CONCLUSIONS: Despite the growing burden of NAFLD, a significant knowledge gap remains for the identification, diagnosis, and management of NAFLD.

Clinical and Patient-Reported Outcomes From Patients With Nonalcoholic Fatty Liver Disease Across the World: Data From the Global Non-Alcoholic Steatohepatitis (NASH)/ Non-Alcoholic Fatty Liver Disease (NAFLD) Registry.

BACKGROUND & AIMS: Globally, nonalcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease. We assessed the clinical presentation and patient-reported outcomes (PROs) among NAFLD patients from different countries. METHODS: Clinical, laboratory, and PRO data (Chronic Liver Disease Questionnaire-nonalcoholic steatohepatitis [NASH], Functional Assessment of Chronic Illness Therapy-Fatigue, and the Work Productivity and Activity Index) were collected from NAFLD patients seen in real-world practices and enrolled in the Global NAFLD/NASH Registry encompassing 18 countries in 6 global burden of disease super-regions. RESULTS: Across the global burden of disease super-regions, NAFLD patients (n = 5691) were oldest in Latin America and Eastern Europe and youngest in South Asia. Most men were enrolled at the Southeast and South Asia sites. Latin America and South Asia had the highest employment rates (>60%). Rates of cirrhosis varied (12%-21%), and were highest in North Africa/Middle East and Eastern Europe. Rates of metabolic syndrome components varied: 20% to 25% in South Asia and 60% to 80% in Eastern Europe. Chronic Liver Disease Questionnaire-NASH and Functional Assessment of Chronic Illness Therapy-Fatigue PRO scores were lower in NAFLD patients than general population norms (all P < .001). Across the super-regions, the lowest PRO scores were seen in Eastern Europe and North Africa/Middle East. In multivariate analysis adjusted for enrollment region, independent predictors of lower PRO scores included younger age, women, and nonhepatic comorbidities including fatigue (P < .01). Patients whose fatigue scores improved over time experienced a substantial PRO improvement. Nearly 8% of Global NAFLD/NASH Registry patients had a lean body mass index, with fewer metabolic syndrome components, fewer comorbidities, less cirrhosis, and significantly better PRO scores (P < .01). CONCLUSIONS: NAFLD patients seen in real-world practices in different countries experience a high comorbidity burden and impaired quality of life. Future research using global data will enable more precise management and treatment strategies for these patients.

Severe impairment of patient-reported outcomes in patients with chronic hepatitis C virus infection seen in real-world practices across the world: Data from the global liver registry.

Cure of chronic hepatitis C (CHC) can lead to improvement of health-related quality of life and other patient-reported outcomes (PROs). While extensive PRO data for CHC patients who were enrolled in clinical trials are available, similar data for patients seen in real-world practices are scarce. Our aim was to assess PROs of CHC patients enrolled from real-world practices from different regions and to compare them with those enrolled in clinical trials. CHC patients seen in clinical practices and not receiving treatment were enrolled in the Global Liver Registry (GLR). Clinical and PRO (FACIT-F, CLDQ-HCV, WPAI) data were collected and compared with the baseline data from CHC patients enrolled in clinical trials. N = 12,171 CHC patients were included (GLR n = 3146, clinical trial subjects n = 9025). Patients were from 30 countries from 6 out of 7 Global Burden of Disease (GBD) super-regions. Compared with clinical trial enrollees, patients from GLR were less commonly enrolled from High-Income GBD super-region, older, more commonly female, less employed, had more type 2 diabetes, anxiety and clinically overt fatigue but less cirrhosis (all p < 0.001). Out of 15 PRO domain and summary scores, 12 were lower in GLR patients than in subjects enrolled in clinical trials (p < 0.001). In multiple regression models, anxiety, depression, and fatigue were associated with significant PRO impairment in CHC patients (p < 0.05). After adjustment for the clinico-demographic confounders, the association of PRO scores of CHC patients with enrolment settings was no longer significant (all p > 0.05). In conclusion, hepatitis C patients seen in the real-world practices have PRO impairment driven by fatigue and psychiatric comorbidities.

Aggregation of Aß40/42 chains in the presence of cyclic neuropeptides investigated by molecular dynamics simulations.

Alzheimer's disease is associated with the formation of toxic aggregates of amyloid beta (Aß) peptides. Despite tremendous efforts, our understanding of the molecular mechanisms of aggregation, as well as cofactors that might influence it, remains incomplete. The small cyclic neuropeptide somatostatin-14 (SST14) was recently found to be the most selectively enriched protein in human frontal lobe extracts that binds Aß42 aggregates. Furthermore, SST14's presence was also found to promote the formation of toxic Aß42 oligomers in vitro. In order to elucidate how SST14 influences the onset of Aß oligomerization, we performed all-atom molecular dynamics simulations of model mixtures of Aß42 or Aß40 peptides with SST14 molecules and analyzed the structure and dynamics of early-stage aggregates. For comparison we also analyzed the aggregation of Aß42 in the presence of arginine vasopressin (AVP), a different cyclic neuropeptide. We observed the formation of self-assembled aggregates containing the Aß chains and small cyclic peptides in all mixtures of Aß42-SST14, Aß42-AVP, and Aß40-SST14. The Aß42-SST14 mixtures were found to develop compact, dynamically stable, but small aggregates with the highest exposure of hydrophobic residues to the solvent. Differences in the morphology and dynamics of aggregates that comprise SST14 or AVP appear to reflect distinct (1) regions of the Aß chains they interact with; (2) propensities to engage in hydrogen bonds with Aß peptides; and (3) solvent exposures of hydrophilic and hydrophobic groups. The presence of SST14 was found to impede aggregation in the Aß42-SST14 system despite a high hydrophobicity, producing a stronger "sticky surface" effect in the aggregates at the onset of Aß42-SST14 oligomerization.

The impact of variants and vaccination on the mortality and resource utilization of hospitalized patients with COVID-19.

BACKGROUND: COVID-19 outcomes among hospitalized patients may have changed due to new variants, therapies and vaccine availability. We assessed outcomes of adults hospitalized with COVID-19 from March 2020-February 2022. METHODS: Data were retrieved from electronic health medical records of adult COVID-19 patients hospitalized in a large community health system. Duration was split into March 2020-June 2021 (pre-Delta period), July-November 2021 (Delta period), and December 2021-February 2022 (Omicron period). RESULTS: Of included patients (n = 9582), 75% were admitted during pre-Delta, 9% during Delta, 16% during Omicron period. The COVID-positive inpatients were oldest during Omicron period but had lowest rates of COVID pneumonia and resource utilization (p < 0.0001); 46% were vaccinated during Delta and 61% during Omicron period (p < 0.0001). After adjustment for demographics and comorbidities, vaccination was associated with lower inpatient mortality (OR = 0.47 (0.34-0.65), p < 0.0001). The Omicron period was independently associated with lower risk of inpatient mortality (OR = 0.61 (0.45-0.82), p = 0.0010). Vaccination and Omicron period admission were also independently associated with lower healthcare resource utilization (p < 0.05). Magnitudes of associations varied between age groups with strongest protective effects seen in younger patients. CONCLUSION: Outcomes of COVID-19 inpatients were evolving throughout the pandemic and were affected by changing demographics, virus variants, and vaccination. KEY POINT: In this observational study of almost 10,000 patients hospitalized from March 2020-February 2022 with COVID-19, age and having multiple comorbidities remained consistent risk factors for mortality regardless of the variant. Vaccination was high in our hospitalized patients. Vaccination conveyed less severe illness and was associated with lower inpatient mortality.