Impact of the COVID-19 pandemic on hospitalizations with hepatocellular carcinoma in the United States.

BACKGROUND: We studied the temporal trends of hepatocellular carcinoma (HCC)-related hospitalizations and potential predictors of in-hospital mortality around the COVID-19 pandemic. RESEARCH DESIGN AND METHODS: Using the International Classification of Diseases code, we used the National Inpatient Sample 2019-2020 and defined HCC and its underlying etiology. To assess the impact of the COVID-19 pandemic on hospitalization and in-hospital mortality, the study period was divided into the pre-COVID-19 era (2019 Q1-2020 Q1) and the COVID-19 era (2020 Q2-2020 Q4). Quarterly trends in etiology-based hospitalizations with HCC and predictors of in-hospital mortality among hospitalizations with HCC were determined. RESULTS: Hospitalization rates for HCC, as well as viral hepatitis-related HCC hospitalization rates, remained stable, while hospitalizations with alcohol-related liver disease (ALD, quarterly percentage change [QPC]: 2.1%; 95% confidence interval [CI]: 0.1%-4.2%) increased steadily. Hospitalization related to nonalcoholic fatty liver disease (NAFLD)-related HCC increased significantly steeper in the COVID-19 era (QPC: 6.6%; 95% CI: 4.0%-9.3%) than in the pre-COVID-19 era (QPC: 0.7%; 95% CI: 0.2%-1.3%). COVID-19 infection was independently associated with in-hospital mortality among hospitalizations with HCC (odds ratio: 1.94, 95% CI: 1.30-2.88). CONCLUSION: Hospitalization rates for viral hepatitis-related HCC remained stable, while those for HCC due to ALD and NAFLD increased during the COVID-19 pandemic.

Causes and risk profiles of mortality among individuals with nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the United States and worldwide. Though nonalcoholic fatty liver per se may not be independently associated with an increased risk for all-cause mortality, it is associated with a number of harmful metabolic risk factors, such as type 2 diabetes mellitus, hyperlipidemia, obesity, a sedentary lifestyle, and an unhealthy diet. The fibrosis stage is a predictor of all-cause mortality in NAFLD. Mortality in individuals with NAFLD has been steadily increasing, and the most common cause-specific mortality for NAFLD is cardiovascular disease, followed by extra-hepatic cancer, liver-related mortality, and diabetes. High-risk profiles for mortality in NAFLD include PNPLA3 I148M polymorphism, low thyroid function and hypothyroidism, and sarcopenia. Achieving weight loss through adherence to a high-quality diet and sufficient physical activity is the most important predictor of improvement in NAFLD severity and the benefit of survival. Given the increasing health burden of NAFLD, future studies with more long-term mortality data may demonstrate an independent association between NAFLD and mortality.

Gallstone Disease and Its Association With Nonalcoholic Fatty Liver Disease, All-Cause and Cause-Specific Mortality.

BACKGROUND & AIMS: Presence of gallstone disease may influence outcomes in patients with nonalcoholic fatty liver disease (NAFLD). We studied the impact of gallstone disease on mortality in individuals with and without NAFLD. METHODS: Prospective cohort study used the Third National Health and Nutrition Examination Survey (1988-1994) with mortality data through 2015. Gallstone disease was defined as ultrasonographic evidence of gallstones or absence of the gallbladder (prior cholecystectomy). NAFLD was defined using standardized ultrasonographic criteria. RESULTS: Gallstone disease and cholecystectomy were independently associated with NAFLD (odds ratio [OR], 1.75; 95% confidence interval [CI], 1.43-2.15 for gallstone disease and OR, 2.77; 95% CI, 2.01-3.83 for cholecystectomy compared with no gallstone disease). During the median follow-up of 23 years, gallstone disease was associated with a higher risk of all-cause mortality (hazard ratio [HR], 1.19; 95% CI, 1.05-1.37) and cause-specific mortality. Gallstone disease was associated with a higher risk of all-cause mortality in non-NAFLD sub-cohort (HR, 1.42; 95% CI, 1.23-1.64) but not in NAFLD (HR, 1.03; 95% CI, 0.87-1.22). Gallstone disease was associated with a higher risk of cardiovascular-related (HR, 1.40; 95% CI, 1.10-1.78) and cancer-related (HR, 1.71; 95% CI, 1.18-2.48) mortality in non-NAFLD sub-cohort. Gallstone disease was associated with increased cardiovascular mortality (HR, 1.36; 95% CI, 1.05-1.77) in NAFLD. CONCLUSIONS: Gallstone disease is an independent risk factor for NAFLD, but gallstone disease is not associated with all-cause mortality in individuals with NAFLD. Screening for gallstone disease in individuals at risk for developing NAFLD may help with risk stratification for all-cause mortality related to gallstone disease.

Physical Activity Is Associated With Nonalcoholic Fatty Liver Disease and Significant Fibrosis Measured by FibroScan.

BACKGROUND AND AIMS: Studies evaluating the association of 2018 Physical Activity Guidelines for Americans (PA Guidelines) with nonalcoholic fatty liver disease (NAFLD) and significant fibrosis or cirrhosis are needed. We evaluated the association of meeting PA Guidelines with NAFLD and significant fibrosis or cirrhosis by transient elastography in the United States. METHODS: A cross-sectional analysis was performed using the 2017-2018 U.S. National Health and Nutrition Examination Survey data. NAFLD and significant fibrosis or cirrhosis were defined by transient elastography in the absence of other causes of chronic liver disease. The detailed PA questionnaire assessed the leisure-time, occupation-related, and transportation-related PA. PA was categorized based on the PA Guidelines. RESULTS: Of the 4304 subjects, leisure-time PA, which met the PA Guidelines (≥150 min/wk), was associated with 44% lower risk of NAFLD (odds ratio [OR]: 0.56; 95% confidence interval [CI]: 0.46-0.67). Subjects who reported 1-2 times (150-299 min/wk) or over 2 times (≥300 min/wk) the recommended amount of PA Guidelines had 40% (OR, 0.60; 95% CI, 0.41-0.90) and 49% (OR, 0.51; 95% CI, 0.40-0.65) lower odds of NAFLD, respectively. Over 8 hours of sitting time had a 44% higher risk of NAFLD (OR, 1.44; 95% CI, 1.01-2.05) when we considered leisure-time PA and sitting time simultaneously. Over 2 times (≥300 min/wk) the recommended amount of PA Guidelines for leisure-time PA had 59% (OR, 0.41; 95% CI, 0.22-0.74) lower risk for significant fibrosis and 63% (OR, 0.37; 95% CI, 0.21-0.64) lower odds of cirrhosis. CONCLUSIONS: Meeting PA Guidelines for leisure-time PA has beneficial effects on NAFLD, and over 2 times the recommended amount of PA Guidelines had lower risk for significant fibrosis or cirrhosis.

Current epidemiology in hepatocellular carcinoma.

INTRODUCTION: Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third-leading cause of cancer-related mortality in the world. AREAS COVERED: This review will discuss risk factors, demographic differences, global trends, and the economic burden of HCC. Viral hepatitis, particularly hepatitis B virus (HBV) infection, is the most common underlying liver disease leading to HCC in those with cirrhosis. Other important risk factors include alcoholic liver disease, nonalcoholic fatty liver disease, metabolic syndrome, etc. With the introduction of direct-acting antiviral agents for hepatitis C virus infection, routine vaccination against HBV, and increasing support for robust public screening programs, the incidence rates for HCC due to viral hepatitis is falling in many countries. Meanwhile, the prevalence of obesity and metabolic syndrome are on the rise, as is NAFLD-related HCC incidence. Asia and Africa have the highest incidence rates of HCC. In multiethnic countries, racial and ethnic minorities experience disparities in HCC incidence as well as mortality, representing an essential area for improvement in terms of healthcare inequity. EXPERT OPINION: Interventions to minimize the global burden of HCC aim to reduce rates of the most common risk factors and implement effective treatment of underlying etiology and comprehensive screening programs for HCC.

Metabolic dysfunction-associated fatty liver disease is associated with increased all-cause mortality in the United States.

BACKGROUND & AIMS: Recently, international experts proposed redefining non-alcoholic fatty liver disease (NAFLD) as metabolic dysfunction-associated fatty liver disease (MAFLD), based on modified criteria. It is suspected that outcomes such as mortality may differ for these clinical entities. We studied the impact of MAFLD and NAFLD on all-cause and cause-specific mortality in US adults. METHODS: We analyzed data from 7,761 participants in the Third National Health and Nutrition Examination Survey and their linked mortality through 2015. NAFLD was diagnosed by ultrasonographic evidence of hepatic steatosis without other known liver diseases. MAFLD was defined based on the criteria proposed by an international expert panel. The Cox proportional hazard model was used to study all-cause mortality and cause-specific mortality between MAFLD and NAFLD, with adjustments for known risk factors. RESULTS: During a median follow-up of 23 years, individuals with MAFLD had a 17% higher risk of all-cause mortality (hazard ratio [HR] 1.17; 95% CI 1.04-1.32). Furthermore, MAFLD was associated with a higher risk of cardiovascular mortality. NAFLD per se did not increase the risk of all-cause mortality. Individuals who met both definitions had a higher risk of all-cause mortality (HR 1.13, 95% CI 1.00-1.26), while individuals who met the definition for MAFLD but not NAFLD had a 1.7-fold higher risk of all-cause mortality (HR 1.66, 95% CI 1.19-2.32). Estimates for all-cause mortality were higher for those with advanced fibrosis and MAFLD than for those with advanced fibrosis and NAFLD. CONCLUSIONS: In this US population-based study, MAFLD was associated with an increased risk of all-cause mortality, while NAFLD demonstrated no association with all-cause mortality after adjusting for metabolic risk factors. LAY SUMMARY: Our findings provide further support for the idea that non-alcoholic fatty liver disease (NAFLD) is a part of a broader multi-system disease that also includes obesity, diabetes, high blood pressure, and high cholesterol. Therefore, re-defining NAFLD as metabolic dysfunction-associated fatty liver disease (MAFLD) may help improve our understanding of predictors that increase the risk of death.

Mortality Trends in Chronic Liver Disease and Cirrhosis in the United States, Before and During COVID-19 Pandemic.

Chronic liver disease (CLD) and cirrhosis accounts for approximately 2 million deaths annually worldwide. CLD and cirrhosis-related mortality has increased steadily in the United States.1,2 With the global pandemic of coronavirus disease 2019 (COVID-19), patients with CLD and cirrhosis represent a vulnerable population at higher risk for complications and mortality.3,4 Although high mortality from COVID-19 among patients with CLD and cirrhosis have been reported,5 national trends in mortality related to CLD and cirrhosis before and during the COVID-19 pandemic have not been assessed. This study estimated the temporal quarterly trends in CLD and cirrhosis-related mortality in the United States from 2017 Q1 to 2020 Q3 using provisional data releases from the National Vital Statistics System.6,7.

Trends in the Mortality of Biliary Tract Cancers Based on Their Anatomical Site in the United States From 2009 to 2018.

INTRODUCTION: Recent trends in the incidence and mortality of biliary tract cancers are unknown. We estimated the trends in biliary tract cancers-related incidence and mortality stratified by anatomical site, age, sex, and race/ethnicity in the US adults. METHODS: We performed a population-based trend analysis using the US national incidence (2009-2017) and mortality records (2009-2018). We identified age-standardized incidence and mortality from intrahepatic cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma, gallbladder cancer, and ampulla of Vater cancer using appropriate ICD-10 code. Temporal mortality was calculated by joinpoint trend analysis with estimates of annual percentage change (APC) described as each trend segment. RESULTS: The incidence rates of ICC increased linearly (APC 8.9%, 95% confidence interval [CI] 7.8%-10.0%) while gallbladder cancer-related incidence rates remained stable early and decreased significantly later in the study (APC -2.8%, 95% CI -5.5% to -0.0% [2014-2017]). Age-standardized mortality from biliary tract cancers steadily increased with an annual increase of 2.0% (95% CI 1.6%-2.3%). Although there was a linear increase in the ICC-related mortality (APC 3.5%, 95% CI 3.1%-3.8%), extrahepatic cholangiocarcinoma-related mortality tended to remain stable earlier and increased later (APC 7.0%, 95% CI 4.6%-9.5% [2013-2018]). By contrast, gallbladder cancer-related mortality steadily decreased over 10 years (APC -1.6%, 95% CI -2.1% to -1.1%). Significant differences in mortality and changes in trends over time were observed in non-Hispanic blacks, Hispanics, and non-Hispanic Asians. DISCUSSION: In this analysis of nationally representative data, changing mortality trends in various biliary tract cancers was noted with a disproportionately higher burden of fatality in minorities.

Rural-Urban Geographical Disparities in Hepatocellular Carcinoma Incidence Among US Adults, 2004-2017.

INTRODUCTION: To evaluate impact of urbanicity and household income on hepatocellular carcinoma (HCC) incidence among US adults. METHODS: HCC incidence was evaluated by rural-urban geography and median annual household income using 2004-2017 Surveillance, Epidemiology, and End Results data. RESULTS: Although overall HCC incidence was highest in large metropolitan regions, average annual percent change in HCC incidence was greatest among more rural regions. Individuals in lower income categories had highest HCC incidence and greatest average annual percent change in HCC incidence. DISCUSSION: Disparities in HCC incidence by urbanicity and income likely reflect differences in risk factors, health-related behaviors, and barriers in access to healthcare services.

Management Approaches to Hepatitis B Virus Vaccination Nonresponse.

Background: Despite the availability of hepatitis B virus (HBV) vaccination, HBV remains a cause of significant morbidity and mortality around the world. Immunologic response and the development of immunity to the HBV vaccine vary significantly among patients. Multiple studies have looked at patients who are at risk of nonresponse and have offered their own approaches to patients who do not respond. This article reviews the best approaches to HBV vaccine nonresponse. Methods: We searched the PubMed database for all articles on HBV vaccination response from 1981 to January 2018. Recommended and tested approaches to nonresponse were identified. Results: A total of 71 adequate-quality studies with 2354 patients were identified. Repeat vaccination with the same dose increased immunologic seroconversion in 85.7% of patients who previously reported nonresponse and in over 80% of patients with end-stage renal disease, HIV infection, hepatitis C virus (HCV) infection, advanced age, hypoalbuminemia, liver cirrhosis, and hemodialysis (HD) dependence. Patients with inflammatory bowel disease, celiac disease, and diabetes had a milder response (67.5%). Increasing the vaccination dose to 40 µg improved seroconversion in HIV-infected, HCV-infected, and HD patients of initial nonresponse. The use of a subcutaneous injection route increased response by 12% in patients infected with HIV. Conclusion: Patients not responding to an initial vaccine series and not actively infected with HBV benefited from reimmunization by repeating the vaccine series or receiving a single-dose vaccine booster. Although the overall response rate was approximately 90% of previous nonresponders, the rate varied among the populations studied.

New Face of Hepatitis C.

Chronic hepatitis C viral (HCV) infection continues to carry a high burden of disease despite recent and emerging advancements in treatment. The persistently high prevalence of HCV is attributed to the rising opioid epidemic, with a history of injection drug use as the primary risk factor for infection. As a result, the epidemiology of HCV-infected individuals is changing. Previously a disease of "Baby Boomers," males, and non-Hispanic blacks, the new generation of patients with HCV includes younger adults from 20 to 39 years of age, both men and women similarly represented, and non-Hispanic whites. Shifting trends in these demographics may be attributed to the use of injection drugs, which also has suggested impact on fibrosis progression in infected individuals. Awareness of the changing face of HCV is necessary to expand and revise recommendations regarding screening, outreach, and care engagement of infected individuals, in order to best identify patients at-risk for infection.

Extrahepatic Manifestations of Primary Biliary Cholangitis.

Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by progressive destruction of the intrahepatic bile ducts, leading to cholestasis. PBC is known to have both hepatic and extrahepatic manifestations. Extrahepatic manifestations are seen in up to 73% of patients with PBC, with the most common being Sjogren's syndrome, thyroid dysfunction and systemic sclerosis. It is thought that patients with PBC are at increased risk of developing these extrahepatic manifestations, almost all of which are autoimmune, because patients with autoimmune disease are at higher risk of developing another autoimmune condition. Due to the high prevalence of extrahepatic diseases in patients with PBC, it is important to complete a thorough medical history at the time of diagnosis. Prompt recognition of extrahepatic disease can lead to improved patient outcomes and quality of life. The following review summarizes the most common extrahepatic conditions associated with PBC.

Medical Management of Metabolic Complications of Liver Transplant Recipients.

Improved short- and long-term survival of liver transplant recipients has led to increased focus on complications of both the early and late posttransplant periods. A variety of metabolic complications have been observed in the post-orthotopic liver transplant population, including hypertension, hyperlipidemia, obesity, diabetes mellitus, nonalcoholic fatty liver disease, and nonalcoholic steatohepatitis. Although only a small proportion of patients experience metabolic complications prior to transplantation, the prevalence of these complications posttransplantation reaches or exceeds that of the general population. This is of particular concern, as cardiovascular disease is the second leading cause of death in the late transplant period. A number of mechanisms mediate these metabolic complications, including reversal of cirrhosis pathophysiology, patient lifestyle factors, and immunosuppressive medications. Titration and modification of immunosuppression have been demonstrated to improve and sometimes even eliminate these conditions. Therefore, given the multiple etiologies contributing to the metabolic derangements, an effective management approach must incorporate lifestyle modifications, immunosuppression titration, and medical management. Best practices and understanding of the mechanisms underlying these complications allow for discussion of initial therapies and strategies; however, further study is necessary to determine the optimal management of metabolic complications over time.

Limited Knowledge of Acetaminophen in Patients with Liver Disease.

Background and Aims: Unintentional acetaminophen overdose remains the leading cause of acute liver failure in the United States. Patients with underlying liver disease are at higher risk of poor outcomes from acetaminophen overdose. Limited knowledge of acetaminophen may be a preventable contributor to elevated rates of overdose and thus acute liver failure. The purpose of this study is to assess knowledge of acetaminophen dosing and presence of acetaminophen in common combination products in patients with liver disease. Methods: We performed a cross-sectional study of patients with liver disease at the Pfleger Liver Institute at the University of California, Los Angeles between June 2015 and August 2016. Patients completed a demographic questionnaire and an acetaminophen knowledge survey. Additional information was obtained from the medical record. Results: Of 401 patients with liver disease, 30 (15.7%) were able to correctly identify that people without liver disease can safely take up to 4 g/day of acetaminophen. The majority of patients (79.9%-86.8%) did not know that Norco® (hydrocone/acetaminophen), Vicodin® (hydrocone/acetaminophen) and Percocet® (oxycodone/acetaminophen) contained acetaminophen. Only 45.3% of the patients knew that Tylenol® #3 contained acetaminophen. Conclusions: We conclude that patients with liver disease have critically low levels of knowledge of acetaminophen, putting them at risk both of acetaminophen overdose, as well as undermedication, and inadequate management of chronic pain. We recommend an increase in education efforts regarding acetaminophen dosage and its safety in the setting of liver disease. Increasing education for those at risk of low acetaminophen knowledge is essential to minimizing acetaminophen overdose rates and optimizing pain management.