Trends in the prevalence of multiple chronic conditions among US adults with hypertension from 1999-2000 through 2017-2020.

BACKGROUND: The prevalence of many chronic conditions has increased over the past several decades among US adults. Many adults with hypertension have other chronic conditions. METHODS: We estimated changes in the age-adjusted prevalence of multiple (≥3) chronic conditions, not including hypertension, using data from the National Health and Nutrition Examination Survey, from 1999-2000 to 2017-2020, among US adults with and without hypertension (24,851 and 24,337 participants, respectively). Hypertension was defined as systolic blood pressure (BP) ≥130 mmHg, diastolic BP ≥80 mmHg, or self-reported antihypertensive medication use. We studied 14 chronic conditions: arthritis, asthma, cancer, coronary heart disease, chronic kidney disease, depression, diabetes, dyslipidemia, hepatitis-B, hepatitis-C, heart failure, lung disease, obesity, and stroke. RESULTS: From 1999-2000 to 2017-2020, the age-adjusted mean number of chronic conditions increased more among US adults with versus without hypertension (2.2 to 2.8 versus 1.7 to 2.0; p-interaction<0.001). Also, the age-adjusted prevalence of multiple chronic conditions increased from 39.0% to 52.0% among US adults with hypertension and from 26.0% to 30.0% among US adults without hypertension (p-interaction=0.022). In 2017-2020, after age, gender, and race/ethnicity adjustment, US adults with hypertension were 1.94 (95% CI: 1.72-2.18) times as likely to have multiple chronic conditions compared to those without hypertension. In 2017-2020, dyslipidemia, obesity, and arthritis were the most common 3 co-occurring chronic conditions among US adults with and without hypertension (age-adjusted prevalence 16.5% and 3.1%, respectively). CONCLUSION: In 2017-2020, more than half of US adults with hypertension had ≥3 additional chronic conditions, a substantial increase from 20 years ago.

Safety-Net Primary Care and Endocrinology Clinicians' Knowledge and Perspectives on Screening for Nonalcoholic Fatty Liver Disease: A Mixed-Methods Evaluation.

OBJECTIVE: Clinical guidelines have expanded the indications for nonalcoholic fatty liver disease (NAFLD) screening to type 2 diabetes mellitus and obesity, which are conditions common in populations who receive care in urban safety-net settings. This study aimed to evaluate safety-net primary care and endocrinology clinicians' knowledge of NAFLD, determine barriers and facilitators to screening, and examine perspectives on the use of electronic health record tools for risk assessment. METHODS: Sequential explanatory mixed methods using survey and qualitative interviews with primary care, primary care subspecialty, and endocrinology clinicians in an urban safety-net health care system. RESULTS: A total of 109 participants completed the survey (36.5% response rate), and 13 participated in interviews. Most respondents underestimated or did not know the prevalence of NAFLD (68%), did not use the recommended noninvasive tests for risk stratification (65%), and few were comfortable with screening for (27%) or managing (17%) NAFLD. Endocrinologists had greater knowledge of risk factors but lower rates of comfort and more often felt that screening was not their responsibility. The qualitative themes included the following: (1) lack of knowledge about screening, (2) concern for underdiagnosing NAFLD, (3) perception of severity impacts beliefs about screening, (4) screening should occur in primary care but is not normative practice, (5) concerns exist about benefit, (6) competing demands with a complex population hinder screening, and (7) a need for easier ways to integrate screening into practice. CONCLUSION: Knowledge gaps may hamper uptake of new guidelines for NAFLD screening in primary care and endocrinology clinics in an urban safety-net health care system. Implementation strategies focused on training and educating clinicians and informed by behavioral economics may increase screening.

NAFLD Associates with Sarcopenia Defined by Muscle Mass and Slow Walking Speed: A Cross-Sectional Analysis from the Framingham Heart Study.

Sarcopenia is associated with NAFLD. It is unknown if the association is explained by shared risk factors. Our study sought to investigate the association between liver fat and sarcopenia in our cohort. Liver fat was measured on CT between 2008 and 2011. We excluded heavy alcohol use and missing covariates. Muscle mass in a subset (n = 485) was measured by 24 h urinary creatinine. Physical function was defined by h strength and walking speed. Sarcopenia was defined as low muscle mass and/or low physical function. We created multivariable-adjusted regression models to evaluate cross-sectional associations between liver fat and low muscle mass, grip strength, and walking speed. The prevalence of hepatic steatosis was 30% (n = 1073; 58.1% women; mean age 65.8 ± 8.6 years). There was a significant positive association between liver fat and muscle mass in linear regression models. The association was not significant after adjusting for BMI. The odds of sarcopenia increased by 28% for each SD in liver fat (OR 1.28; 95% CI 1.02, 1.60) and persisted after accounting for confounders in multivariable-adjusted models (OR 1.30, 95% CI 1.02, 1.67). Further studies are needed to determine if there is a causal relationship between liver fat and sarcopenia and whether treatment of sarcopenia improves liver fat.

Growth Hormone Administration Improves Nonalcoholic Fatty Liver Disease in Overweight/Obesity: A Randomized Trial.

CONTEXT: Overweight and obesity are associated with relative growth hormone (GH) deficiency, which has been implicated in the development of nonalcoholic fatty liver disease (NAFLD). NAFLD is a progressive disease without effective treatments. OBJECTIVE: We hypothesized that GH administration would reduce hepatic steatosis in individuals with overweight/obesity and NAFLD. METHODS: In this 6-month randomized, double-blind, placebo-controlled trial of low-dose GH administration, 53 adults aged 18 to 65 years with BMI ≥25 kg/m2 and NAFLD without diabetes were randomized to daily subcutaneous GH or placebo, targeting insulin-like growth factor 1 (IGF-1) to the upper normal quartile. The primary endpoint was intrahepatic lipid content (IHL) by proton magnetic resonance spectroscopy (1H-MRS) assessed before treatment and at 6 months. RESULTS: Subjects were randomly assigned to a treatment group (27 GH; 26 placebo), with 41 completers (20 GH and 21 placebo) at 6 months. Reduction in absolute % IHL by 1H-MRS was significantly greater in the GH vs placebo group (mean ± SD: -5.2 ± 10.5% vs 3.8 ± 6.9%; P = .009), resulting in a net mean treatment effect of -8.9% (95% CI, -14.5 to -3.3%). All side effects were similar between groups, except for non-clinically significant lower extremity edema, which was more frequent in the GH vs placebo group (21% vs 0%, P = .02). There were no study discontinuations due to worsening of glycemic status, and there were no significant differences in change in glycemic measures or insulin resistance between the GH and placebo groups. CONCLUSION: GH administration reduces hepatic steatosis in adults with overweight/obesity and NAFLD without worsening glycemic measures. The GH/IGF-1 axis may lead to future therapeutic targets for NAFLD.

An international Delphi consensus statement on metabolic dysfunction-associated fatty liver disease and risk of chronic kidney disease.

Background: With the rising global prevalence of fatty liver disease related to metabolic dysfunction, the association of this common liver condition with chronic kidney disease (CKD) has become increasingly evident. In 2020, the more inclusive term metabolic dysfunction-associated fatty liver disease (MAFLD) was proposed to replace the term non-alcoholic fatty liver disease (NAFLD). The observed association between MAFLD and CKD and our understanding that CKD can be a consequence of underlying metabolic dysfunction support the notion that individuals with MAFLD are at higher risk of having and developing CKD compared with those without MAFLD. However, to date, there is no appropriate guidance on CKD in individuals with MAFLD. Furthermore, there has been little attention paid to the link between MAFLD and CKD in the Nephrology community. Methods and Results: Using a Delphi-based approach, a multidisciplinary panel of 50 international experts from 26 countries reached a consensus on some of the open research questions regarding the link between MAFLD and CKD. Conclusions: This Delphi-based consensus statement provided guidance on the epidemiology, mechanisms, management and treatment of MAFLD and CKD, as well as the relationship between the severity of MAFLD and risk of CKD, which establish a framework for the early prevention and management of these two common and interconnected diseases.

Physical Activity and Nonalcoholic Fatty Liver Disease: A Roundtable Statement from the American College of Sports Medicine.

ABSTRACT: Although physical activity (PA) is crucial in the prevention and clinical management of nonalcoholic fatty liver disease, most individuals with this chronic disease are inactive and do not achieve recommended amounts of PA. There is a robust and consistent body of evidence highlighting the benefit of participating in regular PA, including a reduction in liver fat and improvement in body composition, cardiorespiratory fitness, vascular biology, and health-related quality of life. Importantly, the benefits of regular PA can be seen without clinically significant weight loss. At least 150 min of moderate or 75 min of vigorous intensity PA are recommended weekly for all patients with nonalcoholic fatty liver disease, including those with compensated cirrhosis. If a formal exercise training program is prescribed, aerobic exercise with the addition of resistance training is preferred. In this roundtable document, the benefits of PA are discussed, along with recommendations for 1) PA assessment and screening; 2) how best to advise, counsel, and prescribe regular PA; and 3) when to refer to an exercise specialist.

A Healthy Diet is Associated with a Lower Risk of Hepatic Fibrosis.

BACKGROUND: Higher diet quality is associated with a lower risk of NAFLD. OBJECTIVES: We examined the relationship between diet quality and hepatic fibrosis. METHODS: We analyzed cross-sectional associations between 3 a priori diet quality scores-the Dietary Approaches to Stop Hypertension (DASH) score, the Alternative Healthy Eating Index (AHEI), and a modified Mediterranean-style Diet Score (MDS)-and hepatic fat [controlled attenuation parameter (CAP)] and fibrosis [liver stiffness measurement (LSM)] measured by vibration-controlled transient elastography (VCTE) in 2532 Framingham Heart Study (FHS) participants and 3295 participants of the National Health and Nutrition Examination Survey (NHANES). RESULTS: Higher diet quality scores were associated with lower LSM in both FHS and NHANES after adjustment for demographic and lifestyle factors. Additional adjustment for CAP or BMI attenuated the observed associations. Association strength was similar across all 3 diet quality scores. Fixed-effect meta-analysis demonstrated that, under CAP-adjusted models, the LSM decreases associated with 1-SD increase of the DASH, AHEI, and MDS scores were 2% (95% CI: 0.7%, 3.3%; P = 0.002), 2% (95% CI: 0.7%, 3.3%; P = 0.003), and 1.7% (95% CI: 0.7%, 2.6%; P = 0.001), respectively, whereas in the meta-analysis of BMI-adjusted models, LSM reductions associated with 1-SD increase of the DASH, AHEI, and MDS scores were 2.2% (95% CI: -0.1%, 2.2%; P = 0.07), 1.5% (95% CI: 0.3%, 2.7%; P = 0.02), and 0.9 (95% CI: -0.1%, 1.9%; P = 0.07), respectively. CONCLUSIONS: We demonstrated associations of higher diet quality with favorable hepatic fat and fibrosis measures. Our data suggest that a healthy diet may reduce the likelihood of obesity and hepatic steatosis as well as the progression of steatosis to fibrosis.

Clonal haematopoiesis and risk of chronic liver disease.

Chronic liver disease is a major public health burden worldwide1. Although different aetiologies and mechanisms of liver injury exist, progression of chronic liver disease follows a common pathway of liver inflammation, injury and fibrosis2. Here we examined the association between clonal haematopoiesis of indeterminate potential (CHIP) and chronic liver disease in 214,563 individuals from 4 independent cohorts with whole-exome sequencing data (Framingham Heart Study, Atherosclerosis Risk in Communities Study, UK Biobank and Mass General Brigham Biobank). CHIP was associated with an increased risk of prevalent and incident chronic liver disease (odds ratio = 2.01, 95% confidence interval (95% CI) [1.46, 2.79]; P < 0.001). Individuals with CHIP were more likely to demonstrate liver inflammation and fibrosis detectable by magnetic resonance imaging compared to those without CHIP (odds ratio = 1.74, 95% CI [1.16, 2.60]; P = 0.007). To assess potential causality, Mendelian randomization analyses showed that genetic predisposition to CHIP was associated with a greater risk of chronic liver disease (odds ratio = 2.37, 95% CI [1.57, 3.6]; P < 0.001). In a dietary model of non-alcoholic steatohepatitis, mice transplanted with Tet2-deficient haematopoietic cells demonstrated more severe liver inflammation and fibrosis. These effects were mediated by the NLRP3 inflammasome and increased levels of expression of downstream inflammatory cytokines in Tet2-deficient macrophages. In summary, clonal haematopoiesis is associated with an elevated risk of liver inflammation and chronic liver disease progression through an aberrant inflammatory response.

The NAFLD Decompensation Risk Score: External Validation and Comparison to Existing Models to Predict Hepatic Events in a Retrospective Cohort Study.

Background: The NAFLD decompensation risk score (the Iowa Model) was recently developed to identify patients with nonalcoholic fatty liver disease (NAFLD) at highest risk of developing hepatic events using three variables-age, platelet count, and diabetes. Aims: We performed an external validation of the Iowa Model and compared it to existing non-invasive models. Methods: We included 249 patients with NAFLD at Boston Medical Center, Boston, Massachusetts, in the external validation cohort and 949 patients in the combined internal/external validation cohort. The primary outcome was the development of hepatic events (ascites, hepatic encephalopathy, esophageal or gastric varices, or hepatocellular carcinoma). We used Cox proportional hazards to analyze the ability of the Iowa Model to predict hepatic events in the external validation (https://uihc.org/non-alcoholic-fatty-liver-disease-decompensation-risk-score-calculator). We compared the performance of the Iowa Model to the AST-to-platelet ratio index (APRI), NAFLD fibrosis score (NFS), and the FIB-4 index in the combined cohort. Results: The Iowa Model significantly predicted the development of hepatic events with hazard ratio of 2.5 [95% confidence interval (CI) 1.7-3.9, P < 0.001] and area under the receiver operating characteristic curve (AUROC) of 0.87 (CI 0.83-0.91). The AUROC of the Iowa Model (0.88, CI: 0.85-0.92) was comparable to the FIB-4 index (0.87, CI: 0.83-0.91) and higher than NFS (0.66, CI: 0.63-0.69) and APRI (0.76, CI: 0.73-0.79). Conclusions: In an urban, racially and ethnically diverse population, the Iowa Model performed well to identify NAFLD patients at higher risk for liver-related complications. The model provides the individual probability of developing hepatic events and identifies patients in need of early intervention.

American College of Sports Medicine (ACSM) International Multidisciplinary Roundtable report on physical activity and nonalcoholic fatty liver disease.

BACKGROUND AND AIMS: We present findings from the inaugural American College of Sports Medicine (ACSM) International Multidisciplinary Roundtable, which was convened to evaluate the evidence for physical activity as a means of preventing or modifying the course of NAFLD. APPROACH AND RESULTS: A scoping review was conducted to map the scientific literature and identify key concepts, research gaps, and evidence available to inform clinical practice, policymaking, and research. The scientific evidence demonstrated regular physical activity is associated with decreased risk of NAFLD development. Low physical activity is associated with a greater risk for disease progression and extrahepatic cancer. During routine health care visits, all patients with NAFLD should be screened for and counseled about physical activity benefits, including reduction in liver fat and improvement in body composition, fitness, and quality of life. While most physical activity benefits occur without clinically significant weight loss, evidence remains limited regarding the association between physical activity and liver fibrosis. At least 150 min/wk of moderate or 75 min/wk of vigorous-intensity physical activity are recommended for all patients with NAFLD. If a formal exercise training program is prescribed, aerobic exercise with the addition of resistance training is preferred. CONCLUSIONS: The panel found consistent and compelling evidence that regular physical activity plays an important role in preventing NAFLD and improving intermediate clinical outcomes. Health care, fitness, and public health professionals are strongly encouraged to disseminate the information in this report. Future research should prioritize determining optimal strategies for promoting physical activity among individuals at risk and in those already diagnosed with NAFLD.

Longitudinal association between overweight years, polygenic risk and NAFLD, significant fibrosis and cirrhosis.

BACKGROUND: Adiposity amplifies the genetic risk of non-alcoholic fatty liver disease (NAFLD). AIM: We evaluated the association between overweight-years, a cumulative exposure based on the product of the duration and severity of excess body weight (body mass index (BMI) ≥ 25 kg/m2 ), and genetic risk on liver fat and fibrosis. METHODS: This is a longitudinal analysis derived from a prospective cohort of adults in the Framingham Heart Study who underwent genotyping and vibration-controlled-transient-elastography with controlled attenuation parameter. Univariable and multivariable linear and logistic regression analyses were used to assess the association between overweight-years and liver fat and fibrosis. The association between genetic variants of liver fat (PNPLA3, TM6SF2, GCKR) and fibrosis (PNPLA3, TM6SF2, HSD17B13) was also assessed using a polygenic risk score. RESULTS: Our sample included 2478 participants (54% women) with mean age and BMI of 40 (±8.5) years and 26.5(±5.1) kg/m2 , respectively. The mean follow-up was 14(±0.9) years, and each participant underwent three study visits. The prevalence of NAFLD was 28.3% (n = 700), and 207 (8.4%) had clinically significant fibrosis. In age-, sex- and diabetes-adjusted multivariable analyses, overweight-years (per SD) had a strong association with NAFLD (aOR 3.53 [95% CI: 3.10-4.02], p < 0.001), clinically significant fibrosis (aOR 1.60 [95% CI: 1.40-1.84], p < 0.001) and cirrhosis (aOR 1.81 [95% CI: 1.38-2.37], p < 0.001). High-polygenic risk was significantly associated with liver fat and clinically significant fibrosis (p < 0.05). CONCLUSION: Overweight-years is strongly associated with NAFLD and clinically significant fibrosis and combined with polygenic risk may assist in defining the trajectory of NAFLD.

The association between hepatic steatosis and incident cardiovascular disease, cancer, and all-cause mortality in a US multicohort study.

BACKGROUND AND AIMS: NAFLD strongly associates with cardiovascular disease (CVD) risk factors; however, the association between NAFLD and incident CVD, CVD-related mortality, incident cancer, and all-cause mortality is unclear. APPROACH AND RESULTS: We included 10,040 participants from the Framingham Heart Study, the Coronary Artery Risk Development in Young Adults Study, and the Multi-ethnic Study of Atherosclerosis to assess the longitudinal association between liver fat (defined on CT) and incident CVD, CVD-related mortality, incident cancer, and all-cause mortality. We performed multivariable-adjusted Cox regression models including age, sex, diabetes, systolic blood pressure, alcohol use, smoking, HDL, triglycerides, and body mass index at baseline or time-varying covariates. The average age was 51.3±3.3 years and 50.6% were women. Hepatic steatosis was associated with all-cause mortality after 12.7 years of mean follow-up when adjusting for baseline CVD risk factors, including body mass index (HR: 1.21, 1.04-1.40); however, the results were attenuated when utilizing time-varying covariates. The association between hepatic steatosis and incident CVD was not statistically significant after we accounted for body mass index in models considering baseline covariates or time-varying covariates. We observed no association between hepatic steatosis and CVD-related mortality or incident cancer. CONCLUSIONS: In this large, multicohort study of participants with CT-defined hepatic steatosis, accounting for change in CVD risk factors over time attenuated associations between liver fat and overall mortality or incident CVD. Our work highlights the need to consider concurrent cardiometabolic disease when determining associations between NAFLD and CVD and mortality outcomes.

Nonheavy Alcohol Use Associates With Liver Fibrosis and Nonalcoholic Steatohepatitis in the Framingham Heart Study.

BACKGROUND AND AIMS: While heavy alcohol use consistently associates with liver disease, the effects of nonheavy alcohol consumption are less understood. We aimed to investigate the relationship between nonheavy alcohol use and chronic liver disease. METHODS: This cross-sectional study included 2629 current drinkers in the Framingham Heart Study who completed alcohol use questionnaires and transient elastography. We defined fibrosis as liver stiffness measurement (LSM) ≥8.2 kPa. We defined at-risk nonalcoholic steatohepatitis (NASH) as FibroScan-aspartate aminotransferase (FAST) score >0.35 (90% sensitivity) or ≥0.67 (90% specificity). We performed logistic regression to investigate associations of alcohol use measures with fibrosis and NASH, adjusting for sociodemographic and metabolic factors. Subgroup analysis excluded heavy drinkers (>14 drinks per week for women or >21 for men). RESULTS: In this sample (mean age 54.4 ± 8.9 years, 53.3% women), mean LSM was 5.6 ± 3.4 kPa, 8.2% had fibrosis, 1.9% had NASH by FAST ≥0.67, and 12.4% had NASH by FAST >0.35. Participants drank 6.2 ± 7.4 drinks per week. Total drinks per week and frequency of drinking associated with increased odds of fibrosis (adjusted odds ratio [aOR], 1.18; 95% confidence interval [CI], 1.04-1.33; and aOR, 1.08; 95% CI, 1.01-1.16, respectively). Risky weekly drinking, present in 17.4%, also associated with fibrosis (aOR, 1.49; 95% CI, 1.03-2.14). After excluding 158 heavy drinkers, total drinks per week remained associated with fibrosis (aOR, 1.16; 95% CI, 1.001-1.35). Multiple alcohol use measures positively associated with FAST >0.35. CONCLUSIONS: In this community cohort, we demonstrate that nonheavy alcohol use associates with fibrosis and NASH, after adjustment for metabolic factors. Longitudinal studies are needed to determine the benefits of moderating alcohol use to reduce liver-related morbidity and mortality.