GLP-1 Receptor Agonists and Risk for Cirrhosis and Related Complications in Patients With Metabolic Dysfunction-Associated Steatotic Liver Disease.

Importance: Metabolic dysfunction-associated steatotic liver disease (MASLD) is an increasing cause of cirrhosis. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are effective in improving liver inflammation in patients with MASLD. Objective: To determine whether use of GLP-1 RAs is associated with lower risk of developing cirrhosis and its complications, including decompensation and hepatocellular cancer (HCC), among patients with MASLD. Design, Setting, and Participants: This retrospective cohort study with an active comparator, new-user design used data from the national Veterans Health Administration Corporate Data Warehouse and Central Cancer Registry. Patients with MASLD and diabetes who were seen at 130 Veterans Health Administration hospitals and associated ambulatory clinics and who initiated either a GLP-1 RA or dipeptidyl peptidase 4 inhibitor (DPP-4i) between January 1, 2006, and June 30, 2022, were included. Patients were followed up from baseline until one of the study outcomes or the end of the study period (December 31, 2022), whichever came first. Exposures: Each GLP-1 RA new user was propensity score matched in 1:1 ratio to a patient who initiated a DPP-4i during the same month. Separate analyses were conducted among patients without and with cirrhosis at baseline. Main Outcomes and Measures: For patients without cirrhosis, the primary outcome was progression to cirrhosis defined by validated diagnoses codes or a noninvasive marker of liver fibrosis, and secondary outcomes were cirrhosis complications defined both as a composite and individual complications, including decompensation, HCC, or liver transplant, and all-cause mortality. For patients with cirrhosis, the primary outcome was a composite outcome of cirrhosis complications, and secondary outcomes were decompensation, HCC, and all-cause mortality. Results: Of 16 058 patients who initiated GLP-1 RAs, 14 606 did not have cirrhosis (mean [SD] age, 60.56 [10.31] years; 13 015 [89.1%] male), and 1452 had cirrhosis (mean [SD] age, 66.99 [7.09] years; 1360 [93.7%] male) at baseline. These patients were matched to an equal number of patients who initiated a DPP-4i. In patients without cirrhosis, GLP-1 RA use, compared with DPP-4i use, was associated with a lower risk of cirrhosis (9.98 vs 11.10 events per 1000 person-years; hazard ratio [HR], 0.86; 95% CI, 0.75-0.98). Similar results were seen for the secondary outcomes. GLP-1 RA use, compared with DPP-4i use, was associated with a lower risk of the composite outcome of cirrhosis complications (1.89 vs 2.55 events per 1000 person-years; HR, 0.78; 95% CI, 0.59-1.04) and mortality (21.77 vs 24.43 events per 1000 person-years; HR, 0.89; 95% CI, 0.81-0.98). There were no associations between GLP-1 RA use and outcomes in patients with cirrhosis. Conclusions and Relevance: In this cohort study, GLP-1 RA use was associated with a lower risk of progression to cirrhosis and mortality among patients with MASLD and diabetes. The protective association was not seen in patients with existing cirrhosis, underscoring the importance of treatment earlier in the disease course.

Burden of Mortality from Hepatocellular Carcinoma and Biliary Tract Cancers by Race and Ethnicity and Sex in US, 2018-2023.

Backgrounds/Aims: The trends in mortality of hepatocellular carcinoma (HCC) and biliary tract cancers stratified by sex and race/ethnicity in the US continue to evolve. We estimated the sex- and race/ethnicity-based trends in HCC and biliary tract cancers-related mortality in US adults with a focus on disease burden. Methods: We performed a population-based analysis using the US national mortality records from 2018 to 2023. We identified HCC and biliary tract cancer using appropriate ICD-10 codes. Temporal trends in mortality were calculated by joinpoint analysis with annual percentage change (APC). Results: Annual age-standardized mortality from HCC decreased steadily with an APC of -1.4% (95% confidence interval [CI]: -2.0% to -0.7%). While there was a linear increase in intrahepatic cholangiocarcinoma-related mortality (APC: 3.1%, 95% CI: 1.2%-4.9%) and ampulla of Vater cancer-related mortality (APC: 4.1%, 95% CI: 0.5%-7.9%), gallbladder cancer-related mortality decreased (APC: -1.9%, 95% CI: -3.8% to -0.0%). Decreasing trends in mortality from HCC were noted in males, not females. HCC-related mortality decreased more steeply in racial and ethnic minority individuals compared with non-Hispanic White individuals. Racial and ethnic differences in trends in mortality for biliary tract cancers depended on the malignancy's anatomical site. Conclusion: While the annual mortality for HCC- and gallbladder cancer demonstrated declining trends, ICC and AVC-related mortality continued to increase from 2018 to 2023. Although racial and ethnic minority individuals in the US experienced disproportionately higher HCC and biliary tract cancer, recent declines in HCC may be primarily due to declines among racial and ethnic minority individuals and males.

Estimated pulse wave velocity in metabolic dysfunction-associated steatotic liver disease and all-cause/cause-specific mortality.

BACKGROUND AND AIM: Several reports show a significant association between metabolic dysfunction-associated steatotic liver disease (MASLD) and arterial stiffness (estimated pulse wave velocity [ePWV]) as a surrogate marker of vascular age. We investigate whether ePWV as arterial stiffness in MASLD is associated with all-cause/cause-specific mortality. METHODS: This cohort study was based on the third National Health and Nutrition Examination Survey (NHANES, 1988-1994) and NHANES 2007-2014 and linked mortality datasets through 2019. Cox regression models assessed the association between ePWV categorized by quartile and all-cause/cause-specific mortality among individuals with MASLD. RESULTS: During the follow-up of a median of 26.3 years (interquartile range: 19.9-27.9), higher levels of ePWV among individuals with MASLD were associated with increased all-cause mortality, which remained significant after adjusting for demographic, lifestyle, clinical, and metabolic risk factors. Furthermore, higher ePWV in MASLD was associated with higher cardiovascular mortality. There was a 44% (hazard ratio: 1.44, 95% confidence interval: 1.32-1.58) increase in all-cause mortality and a 53% (hazard ratio: 1.53, 95% confidence interval: 1.32-1.77) increase in cardiovascular mortality for every 1 m/s increase in ePWV in MASLD. However, there was no significant association between ePWV and cancer-related mortality. Sensitivity analyses using the NHANES 2007-2014 dataset showed results identical to the original analysis. CONCLUSION: Higher ePWV in MASLD was associated with a higher risk of all-cause and cardiovascular mortality beyond traditional cardiovascular risk factors. Screening for ePWV in individuals with MASLD may be an effective and beneficial approach to reducing all-cause and cardiovascular mortality.

The prevalence and predictors of metabolic dysfunction-associated steatotic liver disease and fibrosis/cirrhosis among adolescents/young adults.

OBJECTIVES: We investigated the current prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) and fibrosis/cirrhosis and identified at-risk populations for MASLD and MASLD-related fibrosis among US adolescents and young adults in the United States. METHODS: Utilizing the National Health and Nutrition Examination Survey 2017-2020, the prevalence of MASLD and fibrosis/cirrhosis was assessed via controlled attenuation parameter (CAP) score and liver stiffness measurements by transient elastography in participants aged 12-29 years with at least one cardiometabolic criteria and absence of other chronic liver disease. Multivariable logistic regression was performed to determine predictors of MASLD and MASLD-related fibrosis. RESULTS: The overall prevalence of MASLD was 23.9% (95% confidence interval [CI]: 21.3-26.5 for CAP ≥ 263 dB/m) and 17.3% (95% CI: 14.7-20.0 for ≥285 dB/m), respectively. The prevalence of fibrosis and cirrhosis in MASLD was 11.0% and 3.1%, respectively. When categorized by age, the prevalence of MASLD varied from 16.8% (of which 6.2% [fibrosis], 1.8% [cirrhosis]) in early and middle adolescents (12-17 years), to 25.5% (11.8% [fibrosis], 4.8% [cirrhosis]) in late adolescents and young adults (18-24 years), and to 30.4% (of which 13.2% [fibrosis] and 2.1% [cirrhosis]) in older young adults (25-29 years). The independent predictors for MASLD included male sex, Hispanic, non-Hispanic Asian, body mass index, and low HDL-cholesterol. In contrast, diabetes and body mass index were associated with an increased risk of fibrosis in individuals with MASLD. CONCLUSIONS: The prevalence of MASLD and related fibrosis in adolescents and young adults in the United States has reached a significant level, with a substantial proportion of cirrhosis.

Steatotic liver disease-associated all-cause/cause-specific mortality in the United States.

BACKGROUND: Recently, a panel of multi-society experts proposed steatotic liver disease (SLD) as an alternative terminology for metabolic dysfunction-associated fatty liver disease (MAFLD) or nonalcoholic fatty liver disease (NAFLD). AIMS: We compared the impact of SLD, subtype of SLD, MAFLD and NAFLD on all-cause and cause-specific mortality. METHODS: A total of 7811 individuals in the third National Health and Nutrition Examination Survey and linked mortality through 2019 were analysed. SLD was defined based on ultrasonographic hepatic steatosis. SLD, subtype of SLD and MAFLD were defined using the proposed definitions. The Cox proportional hazard model assessed all-cause/cause-specific mortality. RESULTS: During a median follow-up of 27.1 years, individuals with SLD and MAFLD experienced approximately 13%-23% higher risk of all-cause mortality (hazard ratio [HR]: 1.15, 95% confidence interval [CI]: 1.02-1.29 for SLD; HR: 1.23, 95% CI: 1.09-1.38 for MAFLD; HR: 1.13, 95% CI: 1.01-1.27 for metabolic dysfunction-associated steatotic liver disease [MASLD]). Individuals with MetALD demonstrated a higher risk of all-cause (HR: 1.68, 95% CI: 1.10-2.57) and cancer-related mortality (HR: 2.40, 95% CI: 1.23-4.66). MASLD with advanced fibrosis had an increased risk of all-cause mortality compared to MASLD without advanced fibrosis. CONCLUSIONS: SLD, especially MASLD and MetALD, is associated with increased all-cause mortality among adults in the US. Given this significant association between SLD or subtype of SLD (MASLD and MetALD) and all-cause mortality, adopting the proposed SLD criteria may help identify a sub-group of individuals with SLD who are at an increased risk for all-cause mortality.

Global prevalence of metabolic dysfunction-associated fatty liver disease-related hepatocellular carcinoma: A systematic review and meta-analysis.

BACKGROUND/AIMS: The global proportion of hepatocellular carcinoma (HCC) attributable to metabolic dysfunction-associated fatty liver disease (MAFLD) is unclear. The MAFLD diagnostic criteria allows objective diagnosis in the presence of steatosis plus defined markers of metabolic dysfunction, irrespective of concurrent liver disease. We aimed to determine the total global prevalence of MAFLD in HCC cohorts (total-MAFLD), including the proportion with MAFLD as their sole liver disease (single-MAFLD), and the proportion of those with concurrent liver disease where MAFLD was a contributary factor (mixed-MAFLD). METHODS: This systematic review and meta-analysis included studies systematically ascertaining MAFLD in HCC cohorts, defined using international expert panel criteria including ethnicity-specific BMI cut-offs. A comparison of clinical and tumour characteristics was performed between single-MAFLD, mixed-MAFLD, and non-MAFLD HCC. RESULTS: 22 studies (56,565 individuals with HCC) were included. Total and single-MAFLD HCC prevalence was 48.7% (95% confidence interval [CI] 34.5-63.0%) and 12.4% (95% CI 8.3-17.3%), respectively. In HCC due to chronic hepatitis B, C, and alcohol-related liver disease, mixed-MAFLD prevalence was 40.0% (95% CI 30.2-50.3%), 54.1% (95% CI 40.4-67.6%) and 64.3% (95% CI 52.7-75.0%), respectively. Mixed-MAFLD HCC had significantly higher likelihood of cirrhosis and lower likelihood of metastatic spread compared to single-MAFLD HCC, and a higher platelet count and lower likelihood of macrovascular invasion compared to non-MAFLD HCC. CONCLUSION: MAFLD is common as a sole aetiology, but more so as a co-factor in mixed-aetiology HCC, supporting the use of positive diagnostic criteria.

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.

Association between food insecurity and metabolic dysfunction-associated steatotic liver disease/significant fibrosis measured by fibroscan.

PURPOSE: Studies evaluating food insecurity and metabolic dysfunction-associated steatotic liver disease (MASLD) and significant hepatic fibrosis are currently scarce. We evaluated the characteristics of food insecure individuals and whether food insecurity was associated with MASLD and significant hepatic fibrosis in the US population. METHODS: In this cross-sectional study from the National Health and Nutrition Examination Survey 2017-2018, 3441 participants with complete data were enrolled. We defined MASLD and significant hepatic fibrosis (≥ F2) by transient elastography in the absence of other causes of liver disease. The detailed questionnaire assessed and categorized food security as high, marginal, low, and very low food security. RESULTS: Food-insecure subjects were more likely to be female, younger, more impoverished, non-Hispanic blacks, Hispanics, and less likely to be educated, married, and physically active. Food insecurity increased the odds of the prevalence of MASLD by 42% (odds ratio [OR]: 1.42, 95% confidence interval [CI]: 1.12-1.78) after adjustment for demographic, lifestyle, and metabolic risk factors. The addition of diabetes and obesity did not change this association (OR: 1.36, 95% CI: 1.03-1.78). The multivariable model showed an independent relationship between food insecurity and significant hepatic fibrosis (OR: 1.40, 95% CI: 1.04-1.88) after adjustment for demographic, lifestyle, and metabolic risk factors, although the association was attenuated and changed insignificantly after adjustment for diabetes and obesity. CONCLUSIONS: Food insecurity was associated with higher odds for MASLD. While there is a relationship between food insecurity and significant hepatic fibrosis, this relationship changed insignificantly after adjustment of diabetes and obesity.

Endogenous sex hormones and nonalcoholic fatty liver disease in US adults.

BACKGROUND AND AIMS: Sex steroid hormones and sex hormone-binding globulin (SHBG) have a role in predisposing individuals to nonalcoholic fatty liver disease (NAFLD), but their effects are known to differ between men and women. The testosterone-to-estradiol ratio (T/E2 ratio) and free androgen index (FAI) were known biomarkers for the hormonal milieu. We investigated whether sex steroid hormones, T/E2 ratio, FAI, and SHBG were associated with NAFLD in US adults. METHODS: A cross-sectional analysis using the 2013-2016 National Health and Nutrition Examination Survey (NHANES) was performed. NAFLD was defined by utilizing the Hepatic Steatosis Index (HSI) and the US fatty liver index (USFLI) without other causes of chronic liver disease. RESULTS: Out of 8687 subjects (49.5% male), low total testosterone levels were associated with progressively higher odds of NAFLD in men. Increasing T/E2 ratio was inversely associated with higher odds of NAFLD in men. Low serum SHBG levels were independently associated with an increased risk of NAFLD regardless of sex and menopausal status. Increasing FAI was independently associated with NAFLD. When we additionally adjusted for SHBG, T/E2 ratio, not total testosterone, was inversely associated with NAFLD in a dose-dependent manner. Increasing FAI was associated with higher odds of NAFLD in premenopausal women and marginally associated with NAFLD in postmenopausal women. CONCLUSION: The T/E2 ratio and SHBG were inversely associated with an increased risk of NAFLD in men. In women, increasing FAI was associated with NAFLD, whereas SHBG was inversely associated with NAFLD.

Using noninvasive clinical parameters to predict mortality and morbidity after cardiac interventions in patients with cirrhosis: A systematic review.

BACKGROUND: Cardiovascular disease commonly affects advanced liver disease patients. They undergo cardiac interventions to improve cardiac outcomes. Cirrhosis increases complication risk, including bleeding, renal and respiratory failure, and further decompensation, including death, posing a clinical dilemma to proceduralists. Predicting outcomes is crucial in managing patients with cirrhosis. Our aim was to systematically review clinical parameters to assess the mortality and complication risk in patients with cirrhosis undergoing cardiac interventions. METHODS: We searched cirrhosis and cardiovascular intervention terminology in PubMed and Excerpta Medica Database (EMBASE) from inception to January 8, 2023. We included studies reporting clinical scores (e.g. Model for End-stage Liver Disease (MELD), Child-Pugh-Turcotte (CPT), cardiovascular interventions, mortality, and morbidity outcomes). We independently abstracted data from eligible studies and performed qualitative summaries. RESULTS: Eight studies met the inclusion criteria. Procedures included tricuspid valve surgery, catheterization-related procedures, aortic valve replacement (AVR), pericardiectomy, and left ventricular assist device (LVAD) placement. MELD primarily predicted mortality (n = 4), followed by CPT (n = 2). Mortality is significantly increased for MELD > 15 after tricuspid valve surgery. Albumin, creatinine, and MELD were significantly associated with increased mortality after transcatheter AVR (TAVR), although specific values lacked stratification. CPT was significantly associated with increased mortality after cardiac catheterization or pericardiectomy. In LVAD placement, increasing MELD increased the unadjusted odds for perioperative mortality. CONCLUSIONS: Our systematic review showed that clinical parameters predict mortality and morbidity risk in patients with cirrhosis undergoing cardiac procedures.

Depression in nonalcoholic fatty liver disease and all-cause/cause-specific mortality.

BACKGROUND: Depression has been associated with nonalcoholic fatty liver disease (NAFLD). Data addressing the impact of depression on NAFLD-related mortality are evolving. We aim to study the association of depression in NAFLD and all-cause/cause-specific mortality in the United States. METHODS: A total of 11,877 individuals with NAFLD in the 2007-2016 National Health and Nutrition Examination Survey with the availability of linked mortality through 2019 were analysed. NAFLD was defined by utilizing the hepatic steatosis index in the absence of known causes of chronic liver disease. Depression and functional impairment due to depression were assessed using the Patient Health Questionnaire. RESULTS: During the median follow-up of 7.6 years, individuals with depression among individuals with NAFLD had a 35% higher all-cause mortality than those without depression (hazard ratio [HR]: 1.35, 95% confidence interval [CI]: 1.03-1.75) after adjusting for demographic, lifestyle and clinical risk factors. NAFLD with functional impairment due to depression had a 62% higher all-cause mortality than NAFLD without functional impairment (HR: 1.62, 95% CI: 1.10-2.39). Depression in NAFLD was associated with an approximately 50% increase in the risk for cardiovascular mortality, with a 2-fold higher cardiovascular mortality in those with functional impairment compared to those without (HR: 2.07, 95% CI: 1.30-3.30). However, there was no significant difference in cancer- and accident-related mortalities in NAFLD with or without depression. CONCLUSIONS: Depression among individuals with NAFLD was associated with a higher risk for all-cause and cardiovascular mortality in the United States.

Exposure to Agent Orange and Hepatocellular Carcinoma Among US Military Personnel.

Importance: Hepatocellular carcinoma (HCC) and its mortality are on the rise. Viral hepatitis and alcohol are leading risk factors; however, other risk factors among veterans are less defined, including Agent Orange (AO), an herbicide linked to several cancers. Objective: To assess the association of AO exposure and HCC in a national cohort of Vietnam veterans. Design, Setting, and Participants: This retrospective cohort study included Vietnam veterans who served between 1966 and 1975, were male, were older than 18 years at the time of deployment, and had established follow-up in the Veterans Affairs (VA) between 2000 and 2019. Veterans with AO exposure were identified in the disability data via validated clinical surveys. Relevant clinical risk factors for cirrhosis and HCC were collected. Patients were stratified based on cirrhosis status, as defined by consecutive diagnosis found by documented International Classification of Diseases, Ninth Revision and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision scores or calculated Fibrosis-4 scores. Data were collected from January 1, 2019, to December 31, 2020, and analyzed from December 2020 to October 2023. Main Outcome and Measures: Incident HCC was the primary outcome. AO and HCC association was estimated using a multivariable Cox regression analysis, with death and liver transplant as competing events. Results: Of the 296 505 eligible veterans (222 545 [75.1%] White individuals and 44 342 [15.0%] Black individuals), 170 090 (57%) had AO exposure (mean [SD] age, 21.62 [3.49] years; 131 552 White individuals [83.2%] and 22 767 Black individuals [14.4%]) and 35 877 (12.1%) had cirrhosis. Veterans who were not exposed to AO were more likely to smoke (109 689 of 126 413 [86.8%] vs 146 061 of 170 090 [85.9%]); use alcohol (54 147 of 126 413 [42.8%] vs 71 951 of 170 090 [42.3%]) and have viral hepatitis (47 722 of 126 413 [37.8%] vs 58 942 of 170 090 [34.7%]). In a multivariable competing risk model, AO exposure was not associated with HCC. Among veterans with cirrhosis, self-identification as Hispanic individuals (aHR, 1.51; 95% CI, 1.30-1.75; P <.001) or Black individuals (aHR, 1.18; 95% CI, 1.05-1.32; P = .004), and having a diagnosis of viral hepatitis (aHR, 3.71; 95% CI, 3.26-4.24; P <.001), alcohol-associated liver disease (aHR, 1.32; 95% CI, 1.19-1.46; P <.001), and nonalcoholic fatty liver disease (NAFLD) (aHR, 1.92; 95% CI, 1.72-2.15; P <.001) were associated with HCC. Among veterans without cirrhosis, hypertension (aHR, 1.63; 95% CI, 1.23-2.15; P <.001) and diabetes (aHR, 1.52; 95% CI, 1.13-2.05; P = .005) were also associated with HCC. Early smoking and alcohol use were significant risk factors for HCC. Conclusions and Relevance: In this large nationwide cohort study of Vietnam veterans, AO exposure was not associated with HCC. Smoking, alcohol, viral hepatitis, and NAFLD were the most important clinical risk factors for HCC.