Severe, Persistent, Disruptive Fatigue Post-SARS-CoV-2 Disproportionately Affects Young Women.

Introduction: Post-acute SARS-CoV-2 (PASC) symptoms are often persistent, disruptive, and difficult to treat effectively. Fatigue is often among the most frequently reported symptoms and may indicate a more challenging road to recovery. Purpose: To describe the natural history, symptomology, and risk profile of long-term post-acute SARS-CoV-2. Patients and Methods: Participants treated for SARS-CoV-2 within a large, community health system in the US were enrolled prospectively in a longitudinal, observational PASC study examining participants at enrollment and 6 months. Medical history, symptom reporting, validated measures of cognition, and patient-reported outcomes (PROs), were performed for all participants and repeated during study follow-up visits. Results: A total of 323 participants completed baseline evaluations. Sixty one participants indicated clinically significant fatigue (23.1% at baseline); a representative sample of 141 enrollees also completed a baseline Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) in-depth fatigue reporting questionnaire, 37 had severe fatigue. The severely fatigued (FACIT-F ≤29.7) were significantly younger, female, had more anxiety and depression, had a higher resting heart rate, reported more sick days, and were less physically active post-COVID. They were more likely to have a diagnosis of chronic kidney disease (13.5% vs 2.9%) but less likely to have a history of cancer (8.1% vs 23.1). Participants who were severely fatigued reported health, diet, weight, and sleep were worse than those not severely fatigued post-COVID (p = 0.02 to 0.0002). Fatigue was significantly correlated with impairment of all PROs administered after COVID-19 infection. Conclusion: Fatigue is a common symptom post-COVID-19 infection and is associated with lower reported well-being and function. Those with severe fatigue tended to be younger and female and have a past medical history of anxiety, depression, kidney disease, and more sedentary lifestyles.

Nonalcoholic Fatty Liver Disease Is Independently Associated With Higher All-Cause and Cause-Specific Mortality.

BACKGROUND & AIMS: The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing globally. We assessed independent associations of NAFLD with all-cause and cause-specific mortality in older community-dwelling adults in the United States. METHODS: Data from the Rancho Bernardo Study cohort, who participated in the research from 1992 to 1996 with mortality data (followed up to July 2019), were analyzed. NAFLD was determined by the improved Fatty Liver Index for the multiethnic US population in the absence of secondary causes of liver disease. Hazard ratios (HRs), 95% CIs, and population-attributable fractions of risk factors on mortality were calculated. Competing-risk analyses of cause-specific mortality were performed. RESULTS: Of the 1523 eligible participants (mean age, 71.8 y; 39.9% male; 99.3% non-Hispanic White; and 10.7% obese), 404 (26.4%) had NAFLD. During 23,311 person-years of follow-up evaluation (mean, 15.22 y; SD, 8.41 y), among NAFLD and non-NAFLD, there were 296 and 717 deaths from all causes, 113 and 263 cardiac deaths, 62 and 112 cancer deaths, and 6 and 2 liver deaths, respectively. NAFLD had a 26% higher all-cause mortality (HR, 1.26; 95% CI, 1.08-1.47) and a 33% (HR, 1.33; 95% CI, 1.04-1.70) and 55% (HR, 1.55; 95% CI, 1.11-2.15) higher cardiac and cancer mortality, respectively, than non-NAFLD. Population-attributable fractions showed 13.9% of deaths, 6.2% of cardiac deaths, and 12.1% of cancer deaths were attributable to NAFLD after adjustments of risk factors (sedentary lifestyle, obesity, hypertension, hyperlipidemia, diabetes). CONCLUSIONS: NAFLD is associated independently with all-cause, cardiac, and cancer mortality. Efforts must continue to raise awareness about NAFLD and develop care pathways and public health efforts to reduce NAFLD burden and associated mortality.

Causes of death in patients with Non-alcoholic Fatty Liver Disease (NAFLD), alcoholic liver disease and chronic viral Hepatitis B and C.

INTRODUCTION AND OBJECTIVES: Cause of mortality in patients with chronic liver diseases (CLDs) may differ based on underlying etiology of liver disease. Our aim was to assess different causes of death in patients with the most common types of CLD using a national database from the United States. MATERIALS AND METHODS: Death data from 2008 and 2018 from the National Vital Statistics System (NVSS) by the National Center for Health Statistics (NCHS) were used. The rank of cause-of-death for each etiology of CLDs was assessed. Causes of death were classified by the ICD-10 codes. Liver-related deaths included liver cancer, cirrhosis and CLDs. RESULTS: Among a total of 2,826,531 deaths in 2018, there were 85,807 (3.04%) with underlying CLD (mean age at death 63.0 years, 63.8% male, 70.8% white). Liver-related mortality was the leading cause of death for all types of CLD [45.8% in non-alcoholic fatty liver disease (NAFLD), 53.0% in chronic hepatitis C (CHC), 57.8% in chronic hepatitis B (CHB), 81.8% in alcoholic liver disease (ALD)]. This was followed by death from cardiac causes (NAFLD 10.3%, CHC 9.1%, CHB 4.6%, ALD 4.2%) and extrahepatic cancer (NAFLD 7.0%, CHC 11.9%, CHB 14.9%, ALD 2.1%). Although liver cancer was the leading cause of cancer death, lung, colorectal and pancreatic cancer were also common causes of cancer death. CONCLUSIONS: Among deceased patients with CLD, underlying liver disease was the leading cause of death. Among solid cancers, liver cancer was the leading cause of cancer-related mortality.

Independent Predictors of Mortality Among Patients With NAFLD Hospitalized With COVID-19 Infection.

The impact of the coronavirus disease 2019 (COVID-19) pandemic among patients with chronic liver disease is unknown. Given the high prevalence of nonalcoholic fatty liver disease (NAFLD), we determined the predictors of mortality and hospital resource use among patients with NAFLD admitted with COVID-19 by using electronic medical records data for adult patients with COVID-19 hospitalized in a multihospital health system who were discharged between March and December 2020. NAFLD was diagnosed by imaging or liver biopsy without other liver diseases. Charlson's comorbidity index (CCI) and Elixhauser comorbidity index (ECI) scores were calculated. In the study sample, among the 4,835 patients hospitalized for COVID-19, 553 had NAFLD (age: 55 ± 16 years, 51% male, 17% White, 11% Black, 58% Hispanic, 8% Asian, 5% from congregated living, 58% obese, 15% morbid obesity [body mass index ≥ 40], 51% type 2 diabetes, 63% hypertension, mean [SD] baseline CCI of 3.9 [3.2], and baseline ECI of 13.4 [11.3]). On admission, patients with NAFLD had more respiratory symptoms, higher body temperature and heart rate, higher alanine aminotransferase and aspartate aminotransferase than non-NAFLD controls (n = 2,736; P < 0.05). Of the patients with NAFLD infected with COVID-19, 3.9% experienced acute liver injury. The NAFLD group had significantly longer length of stay, intensive care unit use, and mechanical ventilation, with a crude inpatient mortality rate of 11%. In multivariate analysis, independent predictors of inpatient mortality among patients with NAFLD infected with COVID-19 were older age, morbid obesity, ECI score ≥ 11, higher Fibrosis-4 Index (FIB-4) score, and oxygen saturation <90% (all P < 0.05), but not sex, race/ethnicity, or any individual comorbidity (all P > 0.05). Conclusion: Patients with NAFLD infected with COVID-19 tend to be sicker on admission and require more hospital resource use. Independent predictors of mortality included higher FIB-4 and multimorbidity scores, morbid obesity, older age, and hypoxemia on admission.

Hospice care utilisation among elderly patients who died with hepatocellular carcinoma in the United States.

BACKGROUND & AIMS: The benefits of hospice care in Medicare recipients with hepatocellular carcinoma (HCC) have not been fully evaluated, which we aimed to study. METHODS: We used nationally representative samples of the Medicare beneficiaries in the USA (2011-2016) to assess the impact of hospice care on the outcomes of patients with HCC. Hospice care benefits on the survival time, length of stay (LOS), 30-day readmissions, and daily charges during the last year and month of life were assessed by logistic regression and generalised linear regression. RESULTS: Among 2,230 Medicare beneficiaries with HCC (mean age, 74.9 years; non-Hispanic White 79.1%; male 66.6%), median survival from HCC diagnosis was 68 days; 556 (24.9%) received hospice services; median hospice LOS was 12 days (4-35 days). Hospice users increased from 20.1% to 31.1% over time, driven by enrolment ≤15 days (45.1-59.2%, respectively). In the last year of life, hospice users (vs. no hospice care) had longer median survival time (76.5 vs. 66 days), lower in-hospital mortality (1.1% vs. 25.5%) and lower median daily charges ($951 vs. $1,004) despite more inpatient admissions and higher comorbid diseases. Hospice enrolment was associated with 48.6% reduction in daily charges (95% CI: -54.9% to -41.5%). Longer hospice LOS was associated with lower rates of healthcare utilisation. Patients with chronic liver disease were less likely to enrol in hospice care (odds ratio = 0.18, 95% CI: 0.14-0.24). CONCLUSIONS: Although hospice provides a significant decrease in healthcare utilisation and some benefit in survival, most care is given in the last 2 weeks of life. Efforts to encourage earlier use of hospice services must continue. LAY SUMMARY: The purpose of hospice care is to provide comfort and lessen suffering at the end of life. Hospice care allows one to die outside the hospital environment which is the wish of most people. However, we found that among persons aged 65 years and older who were diagnosed with liver cancer (which has a poor prognosis), only 25% were enrolled in hospice care and the majority used a hospice only in the last weeks of life. This is a disheartening finding as liver cancer patients with longer hospice enrolment had lower costs and improved survival. We suggest that healthcare practitioners consider discussion of palliative and hospice care routinely with patients suffering from liver cancer.

Contribution of sarcopenia and physical inactivity to mortality in people with non-alcoholic fatty liver disease.

BACKGROUND & AIMS: Physical inactivity and sedentary lifestyle have contributed to the epidemic of obesity and non-alcoholic fatty liver disease (NAFLD). We assessed the association between physical activity, NAFLD, and sarcopenia, and their contributions to mortality. METHODS: Data from the National Health and Nutrition Examination Survey (NHANES) 1999-2004 with Linked Mortality file (through 2015) was utilised. NAFLD was determined by the US Fatty Liver Index in the absence of secondary causes of liver disease. Sarcopenia was defined using appendicular lean mass divided by body mass index by the Foundation for the National Institutes of Health criteria. Activity level was determined using standard self-reports. Publicly available imputed dual-energy X-ray absorptiometry data sets were used. RESULTS: Of 4,611 NHANES participants (48.2% males; 72.5% White; mean age 45.9 years), NAFLD was present in 1,351 (29.3%), of whom 17.7% had sarcopenia. Of the NAFLD group, 46.3% was inactive, whilst intermediate and ideal physical activity rates were observed in 14.2% and 39.5%, respectively. Sarcopenia was significantly and inversely related to higher physical activity level, both amongst NAFLD (odds ratio [OR] = 0.45 [95% CI 0.30-0.69]) and non-NAFLD (OR = 0.51 [0.35-0.75]) groups. During a median follow-up of 13.5 years, a total of 586 subjects died, of whom 251 had NAFLD. Amongst those who died with NAFLD, 33.0% had sarcopenia and 54.3% were inactive. Compared with NAFLD without sarcopenia, NAFLD with sarcopenia was associated with a higher risk of all-cause (hazard ratio [HR] = 1.78 [1.16-2.73]), cardiac-specific (HR = 3.19 [1.17-8.74]), and cancer-specific mortality (HR = 2.12 [1.08-4.15]). CONCLUSIONS: Inactivity is associated with presence of sarcopenia, whilst sarcopenia is associated with increased mortality amongst NAFLD patients. Sarcopenia should be a part of clinical assessment of patients with NAFLD. Treatment of NAFLD should include optimal management of sarcopenia. LAY SUMMARY: Nonalcoholic fatty liver disease (NAFLD) and sarcopenia have similar pathophysiological profiles. Our data show that sarcopenia is associated with inactivity in subjects with NAFLD. The presence of sarcopenia in patients with NAFLD poses increased risk for all-cause and cardiac-specific mortality.

Outcomes of Liver Transplant Candidates with Primary Biliary Cholangitis: The Data from the Scientific Registry of Transplant Recipients.

BACKGROUND: Primary biliary cholangitis (PBC) is progressive and can cause end-stage liver disease necessitating a liver transplant (LT). PBC patients may be disadvantaged on LT waitlist due to MELD-based priority listing or other factors. AIM: The aim was to assess waitlist duration, waitlist mortality, and post-LT outcomes of PBC patients. METHODS: The Scientific Registry of Transplant Recipients data for 1994-2016 was utilized. Adult patients with PBC without hepatocellular carcinoma (HCC) were selected. Their clinico-demographic parameters and waitlist and post-transplant outcomes were compared to those of patients with hepatitis C (HCV) without HCC. RESULTS: Out of 223,391 listings for LT in 1994-2016, 8133 (3.6%) was for PBC without HCC. Mean age was 55.5 years, 76.9% white, 86.2% female, mean MELD score 21, 6.6% retransplants. There were 52,017 patients with hepatitis C included for comparison. The mean waitlist mortality was 17.9% for PBC and 17.6% for HCV (p > 0.05). The average transplantation rate was 57.7% for PBC and 53.3% for HCV (p < 0.0001), while waitlist dropout (death or removal due to deterioration) rate was 25.0% for PBC and 25.4% for HCV (p > 0.05). There was no significant difference in median waiting duration till transplantation between PBC patients and HCV after 2002 (103 vs. 95 days, p > 0.05). Post-LT mortality and graft loss rates were significantly lower in PBC than in HCV patients (all p < 0.02). CONCLUSIONS: Despite no evidence of impaired waitlist outcomes and favorable post-transplant survival in patients with PBC, there is still a high waitlist dropout rate suggesting the presence of an unmet need for effective treatment.

Mortality Related to Nonalcoholic Fatty Liver Disease Is Increasing in the United States.

Population-level nonalcoholic fatty liver disease (NAFLD) death rate data are sparse. We described death rates for adults with NAFLD in the United States using mortality data from the National Vital Statistics System multiple-cause mortality data (2007-2016). Decedents who had NAFLD were identified by International Classification of Diseases (ICD) codes K75.81, K76.0, K74.0, K74.6, and K76.9. Among NAFLD decedents, cause-specific deaths (e.g., cardiovascular disease [CVD], cirrhosis, hepatocellular carcinoma [HCC], non-liver cancer, diabetes mellitus [DM]) were identified by underlying cause of death ICD-10 codes. Trends were evaluated by average annual percentage change (AAPC) in age-standardized death rate (ASDR) per 100,000 persons. Among the 25,129,960 decedents aged ≥20 years, 353,234 (1.4%) decedents had NAFLD (212,322 men; 260,765 non-Hispanic whites, 32,868 non-Hispanic blacks, 46,530 Hispanics, 5,025 non-Hispanic American Indian or Alaska Natives [AIANs], 7,023 non-Hispanic Asian or Pacific Islanders [APIs]), with a mean age at death of 64.47 ± 13.17 years. During the study period, the ASDR for NAFLD increased by 15% (12.94 to 14.90; AAPC, 1.98%; P < 0.001]), while women (AAPC, 2.99% vs. 1.16% men; P = 0.003), non-Hispanic whites (AAPC, 2.48%), non-Hispanic AIANs (AAPC, 2.31%), and Hispanics (AAPC, 0.74%) experienced the highest annual increases. Stable trends were noted for non-Hispanic blacks and non-Hispanic APIs. Among subgroups, Mexican (AAPC, 1.75%) and Asian Indians (AAPC, 6.94%) experienced annual increases. The top six underlying causes of death (155,894 cirrhosis, 38,444 CVD, 19,466 non-liver cancer, 10,867 HCC, 8,113 DM, and 5,683 lung disease) accounted for 67.5% of NAFLD-related deaths. For cause-specific deaths, ASDR increased for HCC (AAPC, 3.82%), DM (AAPC, 2.23%), non-liver cancer (AAPC, 2.14%), CVD (AAPC, 1.59%), and cirrhosis (AAPC, 0.96%). Conclusion: NAFLD-related deaths in U.S. adults are increasing. Cirrhosis is the top cause-specific death, followed by CVD. Women, non-Hispanic whites, and non-Hispanic AIANs (subgroups Mexicans and Asian Indians) experienced the highest increases in deaths. Policies addressing the societal burden of NAFLD are needed.

Direct and Indirect Economic Burden of Chronic Liver Disease in the United States.

BACKGROUND & AIMS: Chronic liver (CLD) is a major public health concern. We assessed its effects on quality of life and work productivity, as well as its economic burden in the United States. METHODS: We performed a cross-sectional study of data from the Medical Expenditure Panel Survey (MEPS; 2004-2013). We extracted participants' sociodemographic parameters and medical histories. Subjects with CLD were identified based on Clinical Classification Software codes. MEPS participants were compared between those with and without CLD, and then between employed and unemployed patients with CLD. Outcomes were quality-of-life scores, employment, and health care use. RESULTS: We collected data from 230,406 adult participants (age, ≥18 y) in the MEPS; 1846 had current CLD (36.7% with viral hepatitis and 5.3% with liver cancer). Individuals with CLD were less likely to be employed (44.7% vs 69.6% patients without CLD), were not working owing to illness/disability (30.5% vs 6.6% without CLD), lost more work because of disability (10.2 vs 3.4 d without CLD), and had more health care use, producing greater health care expenses ($19,390 vs $5567/y without CLD) (all P < .0001). Patients with CLD also had more comorbidities and worse self-reported general and mental health status, and reported more health-related limitations in their daily activities than individuals without CLD (all P < .0001). They also indicated more psychologic distress and depressive symptoms and had a lower quality of life and health utility scores (P < .0001). In multivariate analysis, after adjustment for sociodemographic factors and comorbidities, the presence of CLD was an important predictor of unemployment (odds ratio, 0.60; 95% confidence interval, 0.50-0.70), annual health care expenditure (ß = $9503 ± $2028), and impairment in all aspects of health-related quality of life (all P < .0001). In patients with CLD, the presence of liver cancer had the most profound impact on health care expenditures (ß = $17,278 ± $5726/y) and physical health (ß = -7.2 ± 1.7 for SF-12 physical component) (all P < .005). CONCLUSIONS: In a cross-sectional analysis of MEPS participants, we associated CLD with large economic and quality-of-life burdens.

Long-term outcomes of liver transplantation in patients with hepatitis C infection are not affected by HCV positivity of a donor.

BACKGROUND: The use of HCV-positive livers for HCV-positive recipients is becoming more common. Our aim is to evaluate long-term outcomes in liver transplant recipients transplanted with HCV antibody-positive organs. METHODS: From the Scientific Registry of Transplant Recipients (1995-2013), we selected all adult liver transplant recipients with HCV, and cross-sectionally compared long-term graft loss and mortality rates between those who were transplanted from HCV antibody-positive (HCV+) vs. HCV antibody-negative donors. RESULTS: We included 33,668 HCV+ liver transplant recipients (54.0 ± 7.7 years old, 74.1% male, 71.0% white, 23.6% with liver malignancy). Of those, 5.7% (N = 1930) were transplanted from HCV+ donors; the proportion gradually increased from 2.9% in 1995 to 9.4% in 2013. Patients who were transplanted from HCV+ positive donors were more likely to be discharged alive after transplantation (95.4% vs. 93.9%, p = 0.006), but this difference was completely accounted for by a greater proportion of HCV+ donors in more recent study years (p = 0.10 after adjustment for the transplant year). After transplantation, both mortality in HCV patients transplanted from HCV+ donors (12.5% in 1 year, 24.2% in 3 years, 33.0% in 5 years) and the graft loss rate (2.2% in 1 year, 4.8% in 3 years, 7.5% in 5 years) were similar to those in HCV patients transplanted from HCV-negative donors (all p > 0.05). CONCLUSIONS: Over the past two decades, the use of HCV+ organs for liver transplantation has tripled. Despite this, the long-term outcomes of HCV+ liver transplant recipients transplanted from HCV+ donors were not different from those who were transplanted with HCV-negative organs.