Development of Clinical Algorithm Utilizing Vibration-Controlled Transient Elastography to Detect Advanced Hepatic Fibrosis in Liver Transplant Recipients.

INTRODUCTION: Vibration-controlled transient elastography (VCTE) based liver stiffness measurement (LSM) is an excellent 'rule-out' test for advanced hepatic fibrosis in liver transplant (LT) recipients, however, its ability to 'rule-in' the disease is suboptimal. The study aimed to improve diagnostic performance of LSM in LT recipients. METHODS: Adult LT recipients with a liver biopsy and VCTE were included (N = 150). Sequential covering analysis was performed to create rules to identify patients at low or high risk for advanced fibrosis (stage 3-4). RESULTS: Advanced hepatic fibrosis was excluded in patients with either LSM < 7.45 kPa (n = 72) or 7.45 ≤ LSM < 12.1 kPa and time from LT < 5.6 years (n = 25). Conversely, likelihood of advanced fibrosis was 95% if patients had LSM > 14.1 and controlled attenuation parameter > 279 dB/m (n = 21). Thus, 118 (79%) were correctly identified and 32 (21%) would have required a biopsy to establish the diagnosis. Compared to previously established LSM based cutoff values of 10.5 kPa (Youden index) and 13.3 kPa (maximized specificity), the false positive rates of sequential covering analysis was 1% compared to 16.5% with LSM ≥ 10.5 kPa and 8.3% with LSM ≥ 13.3 kPa. The true positive rates were comparable at 87% for sequential covering analysis, 93% for LSM ≥ 10.5 kPa and 83% for LSM ≥ 13.3 kPa. CONCLUSION: The proposed clinical sequential covering analysis allows for better risk stratification when evaluating for advanced fibrosis in LT recipients compared to LSM alone. Additional efforts are necessary to further reduce the number of patients with indeterminate results in whom a liver biopsy may be required.

Machine-learning model comprising five clinical indices and liver stiffness measurement can accurately identify MASLD-related liver fibrosis.

BACKGROUND & AIMS: aMAP score, as a hepatocellular carcinoma risk score, is proven to be associated with the degree of chronic hepatitis B-related liver fibrosis. We aimed to evaluate the ability of aMAP score for metabolic dysfunction-associated steatotic liver disease (MASLD; formerly NAFLD)-related fibrosis diagnosis and establish a machine-learning (ML) model to improve the diagnostic performance. METHODS: A total of 946 biopsy-proved MASLD patients from China and the United States were included in the analysis. The aMAP score, demographic/clinical indices and liver stiffness measurement (LSM) were included in seven ML algorithms to build fibrosis diagnostic models in the training set (N = 703). The performance of ML models was evaluated in the external validation set (N = 125). RESULTS: The AUROCs of aMAP versus fibrosis-4 index (FIB-4) and aspartate aminotransferase-platelet ratio (APRI) in cirrhosis and advanced fibrosis were (0.850 vs. 0.857 [P = 0.734], 0.735 [P = 0.001]) and (0.759 vs. 0.795 [P = 0.027], 0.709 [P = 0.049]). When using dual cut-off values, aMAP had a smaller uncertainty area and higher accuracy (26.9%, 86.6%) than FIB-4 (37.3%, 85.0%) and APRI (59.0%, 77.3%) in cirrhosis diagnosis. The seven ML models performed satisfactorily in most cases. In the validation set, the ML model comprising LSM and 5 indices (including age, sex, platelets, albumin and total bilirubin used in aMAP calculator), built by logistic regression algorithm (called LSM-plus model), exhibited excellent performance. In cirrhosis and advanced fibrosis detection, the LSM-plus model had higher accuracy (96.8%, 91.2%) than LSM alone (86.4%, 67.2%) and Agile score (76.0%, 83.2%), respectively. Additionally, the LSM-plus model also displayed high specificity (cirrhosis: 98.3%; advanced fibrosis: 92.6%) with satisfactory AUROC (0.932, 0.875, respectively) and sensitivity (88.9%, 82.4%, respectively). CONCLUSIONS: The aMAP score is capable of diagnosing MASLD-related fibrosis. The LSM-plus model could accurately identify MASLD-related cirrhosis and advanced fibrosis.

aMAP Score and Its Combination With Liver Stiffness Measurement Accurately Assess Liver Fibrosis in Chronic Hepatitis B Patients.

BACKGROUND & AIMS: The changes in liver stiffness measurement (LSM) are unreliable to estimate regression of fibrosis during antiviral treatment for chronic hepatitis B (CHB) patients. The age-male-albumin-bilirubin-platelets score (aMAP), as an accurate hepatocellular carcinoma risk score, may reflect the liver fibrosis stage. Here, we aimed to evaluate the performance of aMAP for diagnosing liver fibrosis in CHB patients with or without treatment. METHODS: A total of 2053 patients from 2 real-world cohorts and 2 multicentric randomized controlled trials in China were enrolled, among which 2053 CHB patients were included in the cross-sectional analysis, and 889 CHB patients with paired liver biopsies before and after 72 or 104 weeks of treatment were included in the longitudinal analysis. RESULTS: In the cross-sectional analysis, the areas under the receiver operating characteristic curve of aMAP in diagnosing cirrhosis and advanced fibrosis were 0.788 and 0.757, which were comparable with or significantly higher than those of the fibrosis index based on 4 factors and the aspartate aminotransferase-platelet ratio. The stepwise approach using aMAP and LSM further improved performance in detecting cirrhosis and advanced fibrosis with the smallest uncertainty area (29.7% and 46.2%, respectively) and high accuracy (82.3% and 79.8%, respectively). In the longitudinal analysis, we established a novel model (aMAP-LSM model) by calculating aMAP and LSM results before and after treatment, which had satisfactory performance in diagnosing cirrhosis and advanced fibrosis after treatment (area under the receiver operating characteristic curve, 0.839 and 0.840, respectively), especially for those with a significant decrease in LSM after treatment (vs LSM alone, 0.828 vs 0.748; P < .001 [cirrhosis]; 0.825 vs 0.750; P < .001 [advanced fibrosis]). CONCLUSIONS: The aMAP score is a promising noninvasive tool for diagnosing fibrosis in CHB patients. The aMAP-LSM model could accurately estimate fibrosis stage for treated CHB patients.

Evaluation of liver stiffness measurement-based scores in liver transplantation recipients.

Combining bioclinical parameters with liver stiffness measurement (LSM) has improved the diagnostic performance of vibration-controlled transient elastography (VCTE) for detection of advanced fibrosis in patients with chronic liver disease. However, this approach has not yet been tested in liver transplantation (LT) recipients. Thus, the aim of this study was to evaluate the diagnostic performance of combining LSM-based scores with LSM alone for the detection of advanced fibrosis in LT recipients. Adult LT recipients with a liver biopsy, VCTE, and clinical data necessary to construct LSM-based fibrosis models (FibroScan-AST [FAST], AGILE-3+, and AGILE-4) were included ( n = 132). The diagnostic statistics for advanced fibrosis (fibrosis stage 0-2 vs. 3-4) were determined by optimal cut-off using the Youden index. The area under the receiver operating characteristic curve (AUROC) for LSM was 0.94 (95% confidence interval [95% CI], 0.89-0.99), FAST was 0.65 (95% CI, 0.50-0.79), AGILE-3+ was 0.90 (95% CI, 0.83-0.97), and AGILE-4 was 0.90 (95% CI, 0.83-0.97). No statistically significant differences were noted between the AUROC of LSM versus LSM-based scores. The false-positive rates for AGILE-3+ and AGILE-4 were 14.5% and 11.8% compared with 8.3% for LSM alone. The false-positive rates in LSM-based scores were higher among patients with diabetes mellitus, higher AST levels, and lower platelet counts. The LSM-based scores did not improve the diagnostic performance of LSM alone in LT recipients for the detection of advanced fibrosis. This lack of improvement in diagnostic performance results from the impact of immunosuppression on bioclinical profile and underscores the importance of developing LSM-based scores that are specific to LT patients.

Nonalcoholic Fatty Liver Disease Prevalence Trends Among Adolescents and Young Adults in the United States, 2007-2016.

Understanding the burden of NAFLD among adolescents and young adults has become increasingly relevant. Our aim was to estimate the prevalence of NAFLD among adolescents and young adults in the United States. Data were obtained from National Health and Nutrition Examination Survey from 2007-2016. Adolescents and young adults aged 12 to 29 years were included. NAFLD was determined by the U.S. Fatty Liver Index in the absence of secondary causes of liver disease, and the differences in prevalence trends were analyzed based on age, gender, and race. Complete data were available for 4,654 adolescents and young adults (mean age 21 years; 50.9% male; 56.8% White, 20.9% Hispanic, and 13.3% Black). The overall prevalence of NAFLD among adolescents and young adults was 18.5%, ranging from 13.2% among early and middle adolescents (12-17 years) to 18.7% among late adolescents and young adults (18-24 years), to 24.0% among older young adults (25-30 years) (trend P < 0.001). The prevalence of NAFLD was higher for boys than for girls (aged 12-17: 15.1% vs. 11.3%; aged 18-24: 21.1% vs. 16.2%; aged 25-30: 28.7% vs. 19.2%, all P < 0.030). Among all age groups, Hispanics had a higher prevalence of NAFLD than Whites and Blacks (pairwise P < 0.001). Over the study time period, the prevalence of NAFLD among early and middle adolescents and young adults did not change (trend P > 0.80). In contrast, NAFLD prevalence among late adolescents increased (trend P = 0.018). In fact, White and Hispanic late adolescents were the drivers behind this increase in the prevalence of NAFLD. Conclusion: These data indicate an increasing trend in NAFLD prevalence among 18-24-year-olds. These data have important public health and policy implications.

Poor Awareness of Liver Disease Among Adults With NAFLD in the United States.

Population-based studies that estimate awareness of nonalcoholic fatty liver disease (NAFLD) in the United States are scant. We aimed to understand public awareness of NAFLD and its temporal trends. Our study included 11,700 adults (18+ years old) from five National Health and Nutrition Examination Surveys (2007-2016). NAFLD was determined by the improved Fatty Liver Index for the multiethnic U.S. population (US-FLI) in the absence of secondary causes of liver disease. Overall prevalence of NAFLD, hepatitis C virus, and hepatitis B virus were 36.6%, 1.02% and 0.35%, respectively. From 2007-2008 to 2015-2016, awareness of liver disease among adults with NAFLD improved from 4.4% to 6.3% (trend P = 0.026) but 4 to 10 times lower than awareness about viral hepatitis. In 2015-2016, among adults with NAFLD, awareness of liver disease was lower among young adults (aged 18-29 years) compared with those aged ≥ 30 years (0% vs. 6.9%) and lower among non-Hispanic Blacks compared with other races (0.7% vs. 6.6%) (all P < 0.001). In multivariable analysis, young adults (adjusted odds ratio [aOR] = 0.29; confidence interval [CI] 0.10-0.87) and non-Hispanic Blacks (aOR = 0.43; CI 0.20-0.96) were negatively associated with awareness of liver disease among adults with NAFLD, whereas diabetes (aOR = 2.22; CI 1.37-3.58), advanced fibrosis (aOR = 2.34; CI 1.17-4.68), and a higher number of health care visits (aOR = 1.33; CI 1.15-1.50) were positively associated with awareness of liver disease. Nearly 96% of adults with NAFLD in the United States were unaware they had liver disease, especially among young adults and non-Hispanic Blacks. Findings indicate efforts are needed to improve awareness of NAFLD.

Lactobacillus endocarditis in a healthy patient with probiotic use.

Lactobacilli are commensal anaerobic gram-positive rod organisms that are normal flora of the oral, genitourinary, and gastrointestinal tracts. Lactobacillus rhamnosus is now commonly found in probiotics. They are rarely pathogenic, but occasional cases of bacteremia and associated endocarditis have been noted in patients with pre-disposing factors. We describe a case of Lactobacillus endocarditis in an otherwise healthy patient with probiotic use and gingival laceration and present an accompanying discussion of the potential association of probiotic formulations containing lactobacilli and systemic infection.

Mortality of NAFLD According to the Body Composition and Presence of Metabolic Abnormalities.

Although nonalcoholic fatty liver disease (NAFLD) is associated with obesity, it can also occur in lean and metabolically normal individuals. Our aim was to determine the effect of different combinations of abdominal adiposity and overall adiposity on the mortality of NAFLD. The Third National Health and Nutrition Examination Survey with mortality data from the National Death Index were used. NAFLD was defined as steatosis without other liver diseases. Body composition was categorized according to waist circumference (WC) and body mass index (BMI). Obesity pattern was defined according to BMI (lean, overweight, and obese) and WC (normal and obese) using accepted definitions. The "metabolically abnormal" group had visceral obesity, insulin resistance, type 2 diabetes, hypertension, or hyperlipidemia. Of the 9,341 study individuals (47.9% male; 76.8% white), NAFLD was present in 3,140 (33.6%), of whom 0.6% had lean BMI and normal WC, and 1.7% had lean BMI and obese WC. The prevalence of metabolically normal NAFLD was 3.26% (95% confidence interval [CI]: 2.62%-3.90%), with most of these subjects having lean BMI (79.2%). During an average follow-up of 22.4 years, 24.1% of the subjects died from all causes. Among these deceased individuals, 41.7% had NAFLD at baseline. Causes of death were cardiovascular disease (24.8%), cancer-related (24.3%), type 2 diabetes-related (4.4%), and liver-related (1.7%). Individuals with NAFLD who were lean by BMI but obese by WC had higher risk of all-cause mortality. Individuals with NAFLD with normal BMI but obese WC had a higher risk of cardiovascular mortality (hazard ratio 2.63 [95% CI: 1.15-6.01]) as compared with overweight (by BMI) NAFLD with normal WC. Conclusion: The risk of mortality in NAFLD can be affected by the presence of visceral obesity, especially in the lean BMI group. These data have important management implications for patients with NAFLD.

Extrahepatic manifestations and healthcare expenditures of non-alcoholic fatty liver disease in the Medicare population.

BACKGROUND AND AIM: Non-alcoholic fatty liver disease (NAFLD) is a very common liver disease which has been associated with a number of the extrahepatic manifestations (EHMs) and healthcare expenditures. Our aim was to assess the presence and impact of these EHMs of NAFLD on mortality and healthcare expenditures. METHODS: Medicare beneficiaries (2005-2016) were included. ICD-9 and ICD-10 codes were used to identify patients with NAFLD and EHMs which included cardiovascular disease (CVD), hypertension (HTN), diabetes (DM), hyperlipidemia (HL), non-hepatocellular carcinoma (HCC) cancers, and others. Temporal trends among different groups were analyzed by join point regression model. Independent predictors of outcomes were evaluated in multiple generalized linear or logistic regression models. RESULTS: Among 30,908,679 Medicare beneficiaries (5% sample of Medicare data from 2005-2016), 1,980,950 (6.4%) had NAFLD diagnosis. From 2005 to 2016, the prevalence of NAFLD in the Medicare population increased at an average annual increase of 3.1%. The most common diseases associated with NAFLD were DM (86.3%), followed by HTN (85.2%), HL (79.8%), and CVD (35.8%). One-year mortality rate in NAFLD patients increased from 3.55 to 6.33 per 1000 from 2005 to 2016. One-year mortality was independently associated with diagnosis of HCC, cirrhosis, DM (outpatient), depression, dementia, lung disease, renal failure, thyroid disorder (inpatient), neurological disorder as well as non-HCC cancers. CONCLUSION: NAFLD is associated with a number of EHMs that increases its mortality and increased healthcare expenditure.

No lesion? No problem: case of oesophageal lichen planus in a patient without any cutaneous lesions.

Oesophageal lichen planus (ELP) is an uncommon presentation of mucocutaneous lichen planus. Due to its rare nature, it can often be misdiagnosed. As such, there can be a significant delay between symptom onset and diagnosis. ELP drastically reduces quality of life secondary to the severe dysphagia and odynophagia that typically accompany this pathogenesis. Additionally, it is important to diagnose ELP in a timely manner as ELP increases the risk of squamous cell carcinoma, with reported cases of malignant transformation. More research is needed on ELP with regard to diagnostic criteria and evidence-based therapeutic recommendations.

Epidemiology of Non-alcoholic Fatty Liver Disease in North America.

Nonalcoholic fatty liver disease (NAFLD) is rapidly becoming the most common cause of chronic liver disease worldwide. This is primarily driven by the global epidemic of obesity and diabetes as well as the aging of the general population. Most of the epidemiology data of NAFLD for North America are published from studies originating in the United States (U.S.). The overall prevalence of NAFLD in the U.S. is estimated to be 24%. Hispanic Americans have a higher prevalence of NAFLD, whereas African Americans have a lower prevalence of NAFLD. The exact contributions of genetic and environmental factors on these differences in the prevalence rates have not been determined. From the spectrum of NAFLD, patients with non-alcoholic steatohepatitis (NASH) are at the highest risk of progression to cirrhosis and hepatocellular carcinoma (HCC). The most recent data regarding the progression of NASH suggest a complex pattern of progression and regression of fibrosis. Factors influencing the progression and regression of NASH have not been fully described. More research is needed to better understand NAFLD in Mexico and Canada.

The Relationship Between Hypoadiponectinemia and Cardiovascular Events in Liver Transplant Recipients.

BACKGROUND: Cardiovascular disease (CVD) is an important cause of morbidity and mortality after liver transplantation (LT). Serum adiponectin levels inversely correlate with CVD-related outcomes, but the relationship between hypoadiponectinemia and CVD after LT is unknown. Thus, the aim of the present study was to prospectively evaluate this relationship in LT recipients (LTR). METHODS: LTR were prospectively enrolled (N = 130) between January 1, 2012, and January 1, 2014. Baseline adiponectin levels were drawn at enrollment and patients were followed for CVD events. Hypoadiponectinemia was defined as serum adiponectin <10 µg/mL. The primary endpoint was a composite CVD outcome consisting of myocardial infarction, angina, need for coronary revascularization, stroke, or cardiac death. RESULTS: The mean age was 58 ± 11 years and prevalence of obesity, diabetes, and dyslipidemia was 40%, 35%, and 40%, respectively. A total of 20 CVD events were noted, after median follow up of 45 months. Hypoadiponectinemia was significantly associated with future risk of CVD events (hazard ratio, 3.519; 95% confidence interval, 1.180-10.499, P = 0.024). This association was independent of traditional CVD risk factors including age, gender, obesity, hypertension, diabetes, and choice of immunosuppression. CONCLUSIONS: Hypoadiponectinemia is a strong independent predictor of future cardiovascular events in LTR, which can be incorporated in clinical practice to assess CVD risk assessment after LT.

Small Dense Low-Density Lipoprotein Cholesterol Predicts Cardiovascular Events in Liver Transplant Recipients.

Cardiovascular disease (CVD) is an important cause of morbidity and mortality after liver transplantation (LT). Although LT is associated with dyslipidemia, particularly atherogenic lipoprotein subparticles, the impact of these subparticles on CVD-related events is unknown. Therefore, the aim of the current study was to evaluate the impact of small dense (sdLDL-C) low-density lipoprotein (LDL) cholesterol (LDL-C) on CVD events. Prospectively enrolled patients (N = 130) had detailed lipid profile consisting of traditional lipid parameters and sdLDL-C and were followed for CVD events. The primary endpoint was a CVD composite consisting of myocardial infarction (MI), angina, need for coronary revascularization, and cardiac death. Mean age of the cohort was 58 ± 11 years, and the most common etiology of liver disease (LD) was hepatitis C virus (N = 48) and nonalcoholic steatohepatitis (N = 23). A total of 20 CVD events were noted after median follow-up of 45 months. The baseline traditional profile was similar in patients with and without CVD events. A serum LDL-C cutoff of 100 mg/dL was unable to identify individuals at risk of a CVD event (P = 0.86). In contrast, serum concentration of atherogenic sdLDL-C >25 mg/dL was predictive of CVD events with a hazard ratio of 6.376 (95% confidence interval, 2.65, 15.34; P < 0.001). This relationship was independent of diabetes, hypertension, sex, ethnicity, LD, obesity, and statin use. Conclusion: sdLDL-C independently predicted CVD events whereas LDL-C did not. Thus, sdLDL-C may provide a useful clinical tool in risk stratifying and managing patients after LT.

Prevalence of Nonalcoholic Fatty Liver Disease in the Female Population.

There is a paucity of recent data about the epidemiology and long-term outcomes of nonalcoholic fatty liver disease (NAFLD) in the female population. Our aim was to assess the prevalence, risk factors, and mortality of NAFLD in female adults of the United States. Data from the National Health and Nutrition Examination Survey (NHANES) III and NHANES 1999-2014 were used. NAFLD status was determined by the U.S. Fatty Liver Index (US-FLI) in the absence of other liver diseases and excessive alcohol consumption. The prevalence rates, risk factors, and 5-year all-cause and cardiovascular mortality were determined in women with NAFLD. The most recent prevalence of NAFLD among female adults (2007-2014) in the United States was 24.4% (95% confidence interval [CI], 22.48-26.33). Prevalence was higher among women >44 years of age and those with body mass index ≥30 kg/m2. In addition, the average age of the female population with NAFLD has decreased over time. The fully adjusted odds ratios in women with NAFLD compared to those without NAFLD were 1.48 (95% CI, 1.20-1.82) for cardiovascular disease (CVD), 1.89 (95% CI, 1.42-2.52) for atherosclerotic cardiovascular disease (ASCVD) score ≥7.5%, and 1.76 (95% CI, 1.37-2.25) for either CVD or ASCVD ≥7.5%. The 5-year mortality for female adults with NAFLD was significantly higher than for those without NAFLD (adjusted hazard ratio, 1.48; 95% CI, 1.07-2.05). Among women with NAFLD, those with ASCVD ≥7.5% had significantly higher 5-year all-cause mortality and CVD mortality. Conclusion: The prevalence of NAFLD in female NHANES participants from the United States has continued over recent years. In the female population with NAFLD, ASCVD ≥7.5% is an independent predictor of overall and cardiac-specific mortality.