Pharmaco-Economic Assessment of Screening Strategies for High-Risk MASLD in Primary Care.

BACKGROUND AND AIMS: Several scientific associations recommend a sequential combination of non-invasive tests (NITs) to identify high-risk MASLD patients but their cost-effectiveness is unknown. METHODS: A cost-utility model was developed to assess the incremental cost-effectiveness ratio (ICER) of recommended screening strategies for patients with clinically suspected MASLD, specifically those with type 2 diabetes (T2D) and obesity with multiple cardiometabolic risk factors which will be initiated in primary care. Six screening strategies were assessed, using either vibration-controlled transient elastography (VCTE) or the enhanced liver fibrosis (ELF) test as a second-line test following an initial Fibrosis-4 (FIB-4) assessment as the first line NIT. The model included treatment effects of resmetirom for metabolic dysfunction-associated steatohepatitis (MASH) patients with F2 or F3 fibrosis. RESULTS: All screening strategies for high-risk MASLD in US incurred additional costs compared to no screening, ranging from $13 587 to $14 730 per patient with T2D and $14 274 to $15 661 per patient with obesity. However, screening reduced long-term costs, ranging from $22 150 to $22 279 per patient with T2D and $13 704 to $13 705 per patient with obesity, compared to $24 221 and $14 956 for no screening, respectively. ICERs ranged from $26 913 to $27 884 per QALY for T2D patients and $23 265 to $24 992 per QALY for patients with obesity. While ICERs were influenced by VCTE availability, they remained cost-effective when using ELF as the second-line test. Our findings remain robust across a range of key parameters. CONCLUSIONS: Screening for high-risk MASLD is cost-effective according to recent guidelines. Implementing these screening strategies in primary care should be considered.

Changes in mortality due to Chronic Liver Diseases (CLD) during the COVID-19 pandemic: Data from the United States' National Vital Statistics System.

INTRODUCTION: We assessed chronic liver disease (CLD)-related mortality in the U.S. using death data (2011-2021) obtained from National Vital Statistics System (NVSS). The average annual percentage change (AAPC) from the models selected by Joinpoint regression analysis over the pre-pandemic (2011-2019) and the 2019-2021 were reported because non-linear trend in death rates were observed over the 2011-2021. Liver-specific death was defined as an underlying cause of death and Chronic liver disease (CLD)-related death was defined as any cause of death. During the pre-pandemic, age-standardized HCC- and cirrhosis-specific death rates were annually increased by AAPC = +1.18% (95% confidence interval, 0.34% to 2.03%) and AAPC = +1.95% (1.56% to 2.35%). In contrast, during the 2019-2021, the AAPC in age-standardized cirrhosis-specific death rate (per 100,000) accelerated by up to AAPC +11.25% (15.23 in 2019 to 18.86 in 2021) whereas that in age-standardized HCC-specific death rate slowed to -0.39 (-1.32% to 0.54%) (3.86 in 2019 to 3.84 in 2021). Compared to HCC-specific deaths, cirrhosis-specific deaths were more likely to be non-Hispanic white (72.4% vs. 62.0%) and non-Hispanic American Indian and Alaska native (AIAN) (2.2% vs. 1.1%) and have NAFLD (45.3% vs. 12.5%) and ALD (27.6% vs. 22.0%). During the 2019-2021, the age-standardized HCV- and HBV-related death rate stabilized, whereas the age-standardized NAFLD- and ALD-related deaths rate increased to 20.16 in 2021 (AAPC = +12.13% [7.76% to 16.68%]) and to 14.95 in 2021 (AAPC = +18.30% [13.76% to 23.03%]), which were in contrast to much smaller incremental increases during the pre-pandemic (AAPC = +1.82% [1.29% to 2.35%] and AAPC = +4.54% [3.97% to 5.11%]), respectively). The most pronounced rise in the age-standardized NAFLD-related death rates during the pandemic was observed among AIAN (AAPC = +25.38%), followed by non-Hispanic White female (AAPC = +14.28%), whereas the age-standardized ALD-related death rates during the pandemic were highest among AIAN (AAPC = +40.65%), followed by non-Hispanic Black female (AAPC = +26.79%). CONCLUSIONS: COVID-19 pandemic had a major negative impact on cirrhosis-specific and CLD-related mortality in the U.S. with significant racial and gender disparities.

Association of food insecurity with MASLD prevalence and liver-related mortality.

BACKGROUND & AIMS: The global burden of metabolic dysfunction-associated steatotic liver disease (MASLD) is growing. This study explores the association of food insecurity with MASLD prevalence and liver-related mortality (LRM) across the globe. METHODS: The study combines United Nations' country-level food security data with the MASLD data from the Global Burden of Disease study 2021. Mixed-effects linear regression models, accounting for country-level random effects, were used to assess associations of food security indicators with MASLD prevalence and LRM. The analyses were performed according to each country's socio-demographic index (SDI) status. RESULTS: In 2021, the median MASLD prevalence and liver-related mortality (MASLD-LRM) across 204 countries was 21.77% (14.14%-48.18%) and 2.92 per 100,000 (0.42-10.79) with the highest MASLD prevalence located in North Africa & Middle East (41.70%) and the lowest prevalence in high-income countries (17.31%). After adjustments for age, gender and SDI, higher MASLD prevalence was associated with increasing rates of obesity, type 2 diabetes and low physical activity (p <0.001). When analyses were performed based on SDI status, divergent patterns of MASLD prevalence were observed. In high SDI countries (socioeconomically more developed), MASLD prevalence was significantly higher in those in the top tertile of food insecurity compared to the bottom tertile (mean, 26.73% vs. 18.87%, p = 0.0001). In contrast, in low SDI countries (socioeconomically less developed), the opposite was true (19.45% vs. 24.96%, p = 0.0008). MASLD-LRM was associated with older age, obesity, and metabolic risks (p <0.001). CONCLUSIONS: MASLD prevalence and MASLD-LRM exhibit significant geographical variability, which is influenced by clinicodemographic factors, and food insecurity. Targeted public health strategies which consider the socio-economic realities of each region are essential for mitigating the global burden of MASLD. IMPACT AND IMPLICATIONS: Metabolic dysfunction-associated steatotic liver disease (MASLD) burden varies by region, influenced by food insecurity and healthcare access. In high socio-demographic index (SDI) countries, higher MASLD prevalence is linked to the consumption of low-quality, ultra-processed foods. Public health policies should focus on improving food quality, reducing unhealthy food consumption, and enhancing healthcare access. Conversely, in low SDI countries, while food insecurity can lead to outright deficiencies, the observed lower MASLD prevalence may also be partly attributable to underdiagnosis. In this context, limited healthcare access may have contributed to underestimation of the prevalence of MASLD. Therefore, country-specific policies should address both the issues related to poverty, as well as improving access to diagnostic modalities and healthcare infrastructure to ensure more accurate estimates of cases of MASLD in the specific country. Promoting physical activity is crucial in both high and low SDI countries to manage metabolic conditions associated with MASLD.

The burden of metabolic dysfunction-associated steatotic liver disease and viral hepatitis in Saudi Arabia.

BACKGROUND: Globally, viral hepatitis is decreasing, but nonalcoholic fatty liver disease (NAFLD), now metabolic dysfunction-associated steatotic liver disease (MASLD), is increasing. We assessed the burden and trends of MASLD and viral hepatitis in Saudi Arabia. METHODS: Prevalence, death, and disability data due to MASLD, hepatitis C virus (HCV), and hepatitis B virus (HBV) were obtained from 2019 Global Burden of Disease (GBD) database for Saudi Arabia. Time trends were assessed by annual percent change (APC) from joinpoint regression. RESULTS: From 2012 through 2019, MASLD prevalence in children and adults increased from 28.02% ( n = 8.34 million) to 33.11% ( n = 11.83 million); APC +2.43% (95% confidence interval: 2.33% to 2.54%). HBV prevalence decreased from 1.83% ( n = 0.54 million) to 1.53% ( n = 0.55 million); APC -1.74% (-2.66% to -0.81%). HCV prevalence stabilized from 0.72% ( n = 0.21 million) to 0.73% ( n = 0.26 million): APC +0.32% (-0.13% to 0.78%). Among adults (>20 years), MASLD prevalence increased from 40.64% to 43.95% (APC = +1.15%, 1.12% to 1.18%), HBV prevalence decreased from 2.67% to 2.05% (APC = -2.96%, -3.90% to -2.01%), and HCV leveled from 0.88% to 0.86% (APC = -0.30%, -0.75% to 0.16%). MASLD liver mortality rate from liver cancer and cirrhosis increased: APC of +1.15% (0.82% to 1.48%) from 1.31 to 1.43 (per 100,000). HBV and HCV liver mortality increased at slower rates (APC = +0.78%, 0.38% to 1.19%): 2.07 to 2.20 (per 100,000) and (APC = +0.55%, 0.09% to 0.89%): 6.32 to 6.61 (per 100,000), respectively. CONCLUSIONS: MASLD burden is increasing, while HBV and HCV burden is decreasing/remaining stable. Early prevention and diagnosis health policies for MASLD are needed.

The Global Epidemiology of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis Among Patients With Type 2 Diabetes.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD), now known as metabolic dysfunction associated steatotic liver disease (MASLD), is closely associated with type 2 diabetes (T2D). Our aim was to estimate the most recent global prevalence of NAFLD/MASLD, nonalcoholic steatohepatitis (NASH), now known as metabolic dysfunction associated steatohepatitis (MASH), advanced fibrosis, and mortality among patients with T2D. METHODS: We systematically searched PubMed and Ovid MEDLINE for terms including NAFLD, NASH, and T2D published in 1990-2023 according to PRISMA. The meta-analysis was conducted using a random-effects model. Assessment of bias risk used the Joanna Briggs Institute appraisal tool. RESULTS: From 3134 studies included in the initial search, 123 studies (N = 2,224,144 patients with T2D) were eligible. Another 12 studies (N = 2733 T2D patients with liver biopsy) were eligible for histologic assessments. The global pooled prevalence of NAFLD/MASLD among patients with T2D was 65.33% (95% confidence interval, 62.35%-68.18%). This prevalence increased from 55.86% (42.38%-68.53%) in 1990-2004 to 68.81% (63.41%-73.74%) in 2016-2021 (P = .073). The highest NAFLD/MASLD prevalence among T2D patients was observed in Eastern Europe (80.62%, 75.72%-84.73%), followed by the Middle East (71.24%, 62.22%-78.84%), and was lowest in Africa (53.10%, 26.05%-78.44%). Among patients with liver biopsy data, the global pooled prevalence of NASH/MASH, significant fibrosis, and advanced fibrosis was 66.44% (56.61%-75.02%), 40.78% (24.24%-59.70%), and 15.49% (6.99%-30.99%), respectively. The pooled all-cause mortality was 16.79 per 1000 person-years (PY) (10.64-26.40), 4.19 per 1000 PY (1.34-7.05) for cardiac-specific mortality; 6.10 per 1000 PY (0.78-4.88) for extrahepatic cancer-specific mortality; and 2.15 per 1000 PY (0.00-2.21) for liver-specific mortality. CONCLUSIONS: The prevalence of NAFLD/MASLD among T2D is high and growing. The majority of NAFLD/MASLD patients with T2D have NASH/MASH, and a significant proportion have advanced fibrosis.

Food Insecurity, Low Household Income, and Low Education Level Increase the Risk of Having Metabolic Dysfunction-Associated Fatty Liver Disease Among Adolescents in the United States.

INTRODUCTION: In the United States, 10.2% households (HH) report child food insecurity. We assessed associations between metabolic dysfunction-associated fatty liver disease (MASLD) and food insecurity among the adolescents in the United States. METHODS: This cross-sectional study was performed using data from the National Health and Nutrition Examination Survey 2017-2018. Food insecurity was assessed by the US Department of Agriculture Child Food Security Survey Module. MASLD was defined by transient elastography. RESULTS: Among 771 adolescents (aged 12-18 years) (mean age 14.7 years; 52.5% male; 50.9% White, 12.7% Black, 24.4% Hispanic, and 12.1% other), 9.8% reported food insecurity; MASLD prevalence of 10.12% (95% confidence interval [CI] 7.13%-13.20%) affecting 4.27 million adolescents; and nonalcoholic fatty liver disease prevalence of 10.77% (95% CI 7.76-13.78) affecting 4.52 million adolescents. There was near-perfect concordance between MASLD and nonalcoholic fatty liver disease (Cohen's κ coefficient of 0.971, 95% CI 0.946-0.996). The prevalence of MASLD was greater among food-insecure adolescents vs food-secure ones (17.4% vs 9.4%) and adolescents living with a low HH income vs those with a higher HH income (15.0% vs 7.2%) and living with a head of HH with a lower education level vs one with a higher education level (18.0% vs 8.2%) ( P < 0.05). The fully adjusted model showed that compared with adolescents living in a higher HH income, food-insecure adolescents living in low income HH had a 3-fold greater risk (odds ratio [OR] 3.25, 1.31-8.08) of having MASLD, while food-secure adolescents living in low-income HH had no increased risk (OR 1.58, 0.85-2.93, P = 0.139). The fully adjusted odds of having MASLD was elevated by +163% with the presence of HTN (OR 2.63, 1.02-6.78), +241% with being Hispanic (OR 3.41, 1.36-8.56), and +138% with being male (OR 2.38, 1.20-4.75). In addition, a 1-unit increase in BMI was associated with 25% increase in the odds of having MASLD (OR 1.25, 1.17-1.33) among US adolescents. DISCUSSION: Food insecurity is associated with MASLD among US low-income adolescents especially Hispanic male individuals with obesity and hypertension. Policies addressing inequities are needed.

Prevalence of metabolic dysfunction-associated steatotic liver disease in the Middle East and North Africa.

BACKGROUND AND AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), is common and closely associated with type 2 diabetes (T2D). We assessed the prevalence of NAFLD/MASLD in the general population and among patients with T2D in the Middle East and North Africa (MENA) region. METHODS: We searched PubMed and Embase for English-language articles published between 1990 and 2023 according to PRISMA. Each country's NAFLD/MASLD prevalence in the general population and in T2D patients was predicted by using a multivariable meta regression model. Input data were extracted from our systematic review, GBD and NCD Risk Factor Collaboration. Confidence intervals were constructed by using prediction intervals with the delta method. RESULTS: Meta-analytic pooling estimated the prevalence of NAFLD/MASLD as 39.43% in the general population and 68.71% among T2D patients. NAFLD/MASLD prevalence has increased from 35.42% (2008-2016) to 46.20% (2017-2020). Using GBD-2019 dataset, it was predicted that there are 141.51 million cases of NAFLD/MASLD in the MENA region. The highest number of NAFLD/MASLD cases were expected in Egypt (25.71 million), followed by Türkiye (23.33 million) and Iran (19.85 million). Estimated NAFLD prevalence exceeded 40% in 10 of 21 countries with the top countries being Kuwait (45.37%), Egypt (45.0%), Qatar (44.4%), and Jordan (43.3%). Furthermore, it was predicted that there are 24.96 million cases of NAFLD/MASLD with T2D in the MENA region. CONCLUSIONS: In the MENA region, prevalence of NAFLD/MASLD is very high and growing, necessitating an urgent need for regional public policy to deal with this growing burden.

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.

An International Survey of Genitourinary and Renal Pathologists Regarding Evaluation of the Non-Neoplastic Parenchyma in Kidney Cancer Specimens.

Increasing survivorship in kidney cancer patients has shifted treatment strategies to optimize renal function preservation. In 2010, the College of American Pathologists (CAP) updated their synoptic reporting guidelines for tumor nephrectomies to require evaluation of the nonneoplastic kidney parenchyma. We conducted this study to understand current practice behaviors regarding the evaluation of the nonneoplastic kidney parenchyma in tumor nephrectomy specimens. We emailed a 14-item multiple-choice survey to members of the Renal Pathology Society and Genitourinary Pathology Society. We also emailed a 12-item survey to program and associate program directors of American pathology residencies to assess the current state of renal pathology education. Ninety-eight genitourinary and 104 renal pathologists responded to the survey on the nonneoplastic kidney parenchyma. Ninety-five percent of respondents who examine tumor nephrectomies reported evaluating the nonneoplastic kidney parenchyma. Seventy-five percent of genitourinary pathologists and 67% of renal pathologists use synoptic reporting, and 81% use the CAP protocol. Thirty-nine percent of respondents report always contacting the clinician when they find evidence of medical renal disease. Forty-two program leaders responded to our renal pathology education survey, and 64% of them have a mandatory renal pathology rotation that on average lasts about 2 to 4 weeks. The majority of pathologists examine the nonneoplastic kidney parenchyma of tumor nephrectomies and frequently report incidences of new medical renal disease directly to clinicians, but there remains room for improvement and educational gaps during residency training. Further efforts to standardize both this evaluation and renal pathology education will improve patient care.

The burden of nonalcoholic fatty liver disease (NAFLD) is rapidly growing in every region of the world from 1990 to 2019.

BACKGROUND: The latest meta-analyses suggest NAFLD is increasing globally. Its limitations may preclude accurate estimates. We evaluated the global NAFLD burden and its' trends in prevalence and NAFLD liver-related mortality (LRM) by sex, age, region, and country over the past 3 decades using data from the Global Burden of Disease (GBD) 2019 study. METHODS: Crude and age-standardized NAFLD prevalence and NAFLD-LRM rates were obtained for all-age individuals with NAFLD from 204 countries/territories between 1990 and 2019. Joinpoint trend analysis assessed time trends. Weighted average of the annual percent change (APC) over the period 1990-2019 and 2010-2019 were reported. RESULTS: All-age (children and adults) crude global NAFLD prevalence increased:10.5% (561 million)-16.0% (1,236 million); an APC increase: + 1.47% (95% CI, 1.44%, 1.50%). Among adults (+20 y), crude NAFLD prevalence increased (1990: 17.6%, 2019:23.4%; APC: + 1.00%, 95% CI: 0.97%, 1.02%). In all-age groups, the crude NAFLD-LRM rate (per 100,000) increased (1990: 1.75%, 2019: 2.18%; APC: + 0.77% (95% CI, 0.70%, 0.84%). By Joinpoint analysis, from 2010 to 2019, worsening all-age trends in NAFLD prevalence and LRM were observed among 202 and 167 countries, respectively. In 2019, there were 1.24 billion NAFLD prevalent cases and 168,969 associated deaths; Asia regions accounted for 57.2% of all-age prevalent cases and 46.2% of all-age NAFLD-LRM. The highest all-age crude NAFLD prevalence rate was the Middle East and North Africa (LRM 26.5%); the highest all-age crude NAFLD-LRM rate was Central Latin America (5.90 per 100,000). CONCLUSIONS: NAFLD is increasing globally in all-age groups-over 80% of countries experienced an increase in NAFLD and NAFLD-LRM. These data have important policy implications for affected countries and for global health.

Evidence for an association of serum microanalytes and myofascial pain syndrome.

BACKGROUND: Myofascial Pain Syndrome (MPS) is a common pain disorder. Diagnostic criteria include physical findings which are often unreliable or not universally accepted. A precise biosignature may improve diagnosis and treatment effectiveness. The purpose of this study was to assess whether microanalytic assays significantly correlate with characteristic clinical findings in people with MPS. METHODS: This descriptive, prospective study included 38 participants (25 women) with greater than 3 months of myofascial pain in the upper trapezius. Assessments were performed at a university laboratory. The main outcome measures were the Beighton Index, shoulder range of motion, strength asymmetries and microanalytes: DHEA, Kynurenine, VEGF, interleukins (IL-1b, IL-2, IL-4, IL-5, IL-7, IL-8, IL-13), growth factors (IGF-1, IGF2, G-CSF, GM-CSF), MCP-1, MIP-1b, BDNF, Dopamine, Noradrenaline, NPY, and Acetylcholine. Mann-Whitney test and Spearman's multivariate correlation were applied for all variables. The Spearman's analysis results were used to generate a standard correlation matrix and heat map matrix. RESULTS: Mean age of participants was 32 years (20-61). Eight (21%) had widespread pain (Widespread Pain Index ≥ 7). Thirteen (34%) had MPS for 1-3 years, 14 (37%) 3-10 years, and 11 (29%) for > 10 years. The following showed strong correlations: IL1b,2,4,5,7,8; GM-CSF and IL 2,4,5,7; between DHEA and BDNF and between BDNF and Kynurenine, NPY and acetylcholine. The heat map analysis demonstrated strong correlations between the Beighton Index and IL 5,7, GM-CSF, DHEA. Asymmetries of shoulder and cervical spine motion and strength associated with select microanalytes. CONCLUSION: Cytokine levels significantly correlate with selected clinical assessments. This indirectly suggests possible biological relevance for understanding MPS. Correlations among some cytokine clusters; and DHEA, BDNF kynurenine, NPY, and acetylcholine may act together in MPS. These findings should be further investigated for confirmation that link these microanalytes with select clinical findings in people with MPS.

Nonalcoholic fatty liver disease mortality may not be decreasing: A need for careful interpretation of GBD 2019 estimates of liver deaths.

The Global Burden of Disease (GBD) data provide information on population health; however, careful understanding of the estimation methods and limitations of these data is critical. Herein, Paik et al. discuss the recent study by Chew and colleagues in the context of these limitations, highlighting how a worsening trend in NAFLD-liver mortality may have been underestimated in the analysis.

Nonalcoholic fatty liver disease (NAFLD) and associated mortality in individuals with type 2 diabetes, pre-diabetes, metabolically unhealthy, and metabolically healthy individuals in the United States.

BACKGROUND: The prevalence of nonalcoholic fatty liver disease (NAFLD) is high among subjects with type 2 diabetes (T2D). However, the prevalence and outcomes of NAFLD among individuals with pre-diabetes (PreD) and metabolically healthy and metabolically unhealthy individuals without T2D are not known. Our aim was to assess prevalence and mortality of NAFLD among these four groups. METHODS: The Third National Health and Nutrition Examination Survey (NHANES) III (1988-1994) with mortality data (follow up to 2019) via linkage to the National Death Index was utilized. NAFLD was defined by ultrasound and absence of other liver diseases and excess alcohol use. Pre-D was defined as fasting plasma glucose values of 100-125 mg/dL and/or HbA1c level between 5.7 %-6.4 % in the absence of established diagnosis of T2D. Metabolically healthy (MH) was defined if all of the following criteria were absent: waist circumference of ≥102 cm (men) or ≥ 88 cm (women) or BMI of ≥30; blood pressure (BP) ≥ 130/85 mmHg or using BP-lowering medication; triglyceride level ≥ 150 mg/dL or using lipid-lowering medication; lipoprotein cholesterol level of <40 mg/dL (men) or < 50 mg/dL (women); homeostasis model assessment of insulin resistance (HOMA-IR) score ≥ 2.5; C-reactive protein (CRP) level of >2 mg/L; Pre-D and T2D. Metabolically unhealthy (MU) individuals were defined as the presence of any component of metabolic syndrome but not having Pre-D and T2D. Competing risk analyses of cause-specific mortality were performed. FINDINGS: 11,231 adults (20-74y) were included: mean age 43.4 years; 43.9 % male; 75.4 % white, 10.8 % Black, and 5.4 % Mexican American, 18.9 % NAFLD, 7.8 % T2D; 24.7 % PreD; 44.3 % MU; and 23.3 % in MH individuals. In multivariable adjusted logistic model, as compared to MH individuals, the highest risk of having NAFLD were in T2D individuals (Odd Ratio [OR] = 10.88 [95 % confidence interval: 7.33-16.16]), followed by Pre-D (OR = 4.19 [3.02-5.81]), and MU (OR = 3.36 [2.39-4.71]). During a median follow up of 26.7 years (21.2-28.7 years), 3982 died. NAFLD subjects had significantly higher age-adjusted mortality than non-NAFLD (32.7 % vs. 28.7 %, p < .001). Among subjects with NAFLD, the highest age-standardized cumulative mortality was observed among those with T2D (41.3 %), followed by with Pre-D (35.1 %), MU subjects (30.0 %), and MH subjects (21.9 %) (pairwise p-values<.04 vs. MH). Multivariable adjusted cox models showed that NAFLD with T2D had a higher risk of all-causes and cardiac-specific deaths (Hazard Ratio [HR] = 4.71 [2.23-9.96] and HR = 20.01 [3.00-133.61]), followed by NAFLD with Pre-D (HR = 2.91 [1.41-6.02] and HR = 10.35 [1.57-68.08]) and metabolically unhealthy NAFLD (HR = 2.59 [1.26-5.33] and HR = 6.74 [0.99-46.03]) compared to metabolically healthy NAFLD. In addition to older age, independent predictors of mortality among NAFLD with T2D included high CRP, CVD, CKD, high FIB-4, and active smoking. Similarly, among NAFLD with PreD, high CRP, CKD, CVD, hypertension, and active smoking were associated with mortality. Finally, CVD and active smoking were predictors of mortality among metabolically unhealthy NAFLD, and active smoking was the only mortality risk among metabolically healthy NAFLD subjects. INTERPRETATION: Metabolic abnormality impacts both prevalence and outcomes of subjects with NAFLD.

The Growing Economic and Clinical Burden of Nonalcoholic Steatohepatitis (NASH) in the United States.

Background: Nonalcoholic steatohepatitis (NASH) is a cause of chronic liver disease. Aim: Model the burden of NASH in the United States according to obesity. Methods: The discrete-time Markov model comprised adult NASH subjects moving through 9 health states and 3 absorbing death states (liver, cardiac, and other deaths) with 1-year cycles and a 20-year horizon. Given that reliable natural history data for NASH are not available, transition probabilities were estimated from the literature and population-based data. These rates were disaggregated to determine age-obesity group rates by applying estimated age-obesity patterns. The model considers 2019 prevalent NASH cases and new incident NASH cases (2020-2039), assuming that recent trends will continue. Annual per-patient costs by health state were based on published data. Costs were standardized to 2019 US dollars and inflated by 3% annually. Results: NASH cases in the United States are forecasted to increase by +82.6%, from 11.61 million (2020) to 19.53 million (2039). During the same period, cases of advanced liver disease increased +77.9%, from 1.51 million to 2.67 million, while its proportion remained stable (13.46%-13.05%). Similar patterns were observed in both obese and non-obese NASH. Among NASH, 18.71 million overall deaths, 6.72 million cardiac-specific deaths, and 1.71 million liver-specific deaths were observed by 2039. During this period, the projected cumulative direct healthcare costs were $1208.47 billion (obese NASH) and $453.88 billion (non-obese NASH). By 2039, the projected NASH attributable healthcare cost per patient increased from $3636 to $6968. Conclusions: There is a substantial and growing clinical and economic burden of NASH in the United States.

Non-alcoholic fatty liver disease is associated with greater risk of 30-day hospital readmission in the United States (U.S.).

INTRODUCTION AND OBJECTIVES: Data about 30-day readmission for patients with chronic liver disease (CLD) and their contribution to CLD healthcare burden are sparse. Patterns, diagnoses, timing and predictors of 30-day readmissions for CLD from 2010-2017 were assessed. MATERIALS AND METHODS: Nationwide Readmission Database (NRD) is an all-payer, all-ages, longitudinal administrative database, representing 35 million discharges in the US population yearly. We identified unique patients discharged with CLD including hepatitis B (HBV) and C (HCV), alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) from 2010 through 2017. Survey-weight adjusted multivariable analyses were used. RESULTS: From 2010 to 2017, the 30-day readmission rate for CLD decreased from 18.4% to 17.8% (p=.008), while increasing for NAFLD from 17.0% to 19. 9% (p<.001). Of 125,019 patients discharged with CLD (mean age 57.4 years, male 59.0%) in 2017, the most common liver disease was HCV (29.2%), followed by ALD (23.5%), NAFLD (17.5%), and HBV (4.3%). Readmission rates were 20.5% for ALD, 19.9% for NAFLD, 16.8% for HCV and 16.7% for HBV. Compared to other liver diseases, patients with NAFLD had significantly higher risk of 30-day readmission in clinical comorbidities adjusted model (Hazard ratio [HR]=1.08 [95% confidence interval 1.03-1.13]). In addition to ascites, hepatic encephalopathy, higher number of coexisting comorbidities, comorbidities associated with higher risk of 30-day readmission included cirrhosis for NALFD and HCV; acute kidney injury for NAFLD, HCV and ALD; HCC for HCV, and peritonitis for ALD. Cirrhosis and cirrhosis-related complications were the most common reasons for 30-day readmission, followed by sepsis. However, a large proportion of patients (43.7% for NAFLD; 28.4% for HCV, 39.0% for HBV, and 29.1% for ALD) were readmitted for extrahepatic reasons. Approximately 20% of those discharged with CLD were readmitted within 30 days but the majority of readmissions occurred within 15 days of discharge (62.8% for NAFLD, 63.7% for HCV, 74.3% for HBV, and 72.9% for ALD). Among readmitted patients, patients with NAFLD or HCV readmitted ≤30-day had significantly higher costs and risk of in-hospital mortality (NAFLD +5.69% change [95% confidence interval, 2.54%-8.93%] and odds ratio (OR)=1.58 [1.28-1.95]; HCV +9.85% change [95%CI:6.96%-12.82%] and OR=1.31, 1.08-1.59). CONCLUSIONS: Early readmissions for CLD are prevalent causing economic and clinical burden to the US healthcare system, especially NAFLD readmissions. Closer surveillance and attention to both liver and extrahepatic medical conditions immediately after CLD discharge is encouraged.

Sarcopenia Among Patients With Nonalcoholic Fatty Liver Disease (NAFLD) Is Associated With Advanced Fibrosis.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) and sarcopenia can be associated with advanced liver disease. Our aim was to assess the association between sarcopenia and the risk of fibrosis among patients with NAFLD. METHODS: We used the National Health and Nutrition Examination Survey (2017-2018). NAFLD was defined by transient elastography without other causes of liver disease or excessive alcohol use. Significant fibrosis (SF) and advanced fibrosis (AF) were defined by liver stiffness greater than 8.0 kPa and greater than 13.1 kPa, respectively. Sarcopenia was defined using the Foundation for the National Institutes of Health definition. RESULTS: Of the total cohort (N = 2422), 18.9% had sarcopenia, 9.8% had obese sarcopenia, 43.6% had NAFLD, 7.0% had SF, and 2.0% had AF. Moreover, 50.1% had neither sarcopenia nor NAFLD, 6.3% had sarcopenia without NAFLD, 31.1% had NAFLD without sarcopenia, and 12.5% had NAFLD with sarcopenia. Compared with individuals without NAFLD or sarcopenia, individuals with sarcopenic NAFLD had higher rates of SF (18.3% vs 3.2%) and AF (7.1% vs 0.2%). In the absence of sarcopenia, compared with individuals without NAFLD, individuals with NAFLD have a significantly increased risk of SF (odds ratio, 2.18; 95% CI, 0.92-5.19). In the presence of sarcopenia, NAFLD was associated with an increased risk of SF (odds ratio, 11.27; 95% CI, 2.79-45.56). This increase was independent of metabolic components. The proportion of SF that is attributable to the interaction of NAFLD and sarcopenia was 55% (attributable proportion, 0.55; 95% CI, 0.36-0.74). Increased leisure time physical activity was associated with a lower risk of sarcopenia. CONCLUSIONS: Patients with sarcopenic NAFLD are at risk for SF and AF. Increased physical activity and a healthy diet targeted to improve sarcopenic NAFLD could reduce the risk of significant fibrosis.