MASLD/MetALD and mortality in individuals with any cardio-metabolic risk factor: A population-based study with 26.7 years of follow-up.

BACKGROUND AND AIMS: A new term, metabolic dysfunction-associated steatotic liver disease (MASLD), has been proposed by a multi-society expert panel. However, it remains unclear whether hepatic steatosis per se in MASLD contributes to an increased risk of mortality in individuals with any cardio-metabolic risk factor (CMRF), which is also a significant risk factor for increased mortality. This study aimed to compare all-cause and cause-specific mortality between the "MASLD/MetALD" and "no steatotic liver disease (SLD)" groups in individuals with any CMRF. APPROACH AND RESULTS: A population-based cohort study was conducted using 10,750 participants of the Third National Health and Nutrition Examination Survey. All-cause and cause-specific (cardiovascular, cancer, diabetes, and liver) mortality risks were compared between the "MASLD," "MetALD," and "no SLD" groups using the Cox proportional hazards model with complex survey design weights, adjusted for confounders. Over 26 years, the "MASLD" group did not show significantly increased all-cause (adjusted HR 1.04[95% CI: 0.95-1.14], p = 0.413), cardiovascular (0.88 [0.75-1.04], p = 0.139), or cancer (1.06[0.84-1.33], p = 0.635) mortality risk compared to the "no SLD" group in individuals with any CMRF. The MetALD group was associated with increased all-cause (1.41 [1.05-1.89], p = 0.022), cancer (2.35 [1.33-4.16], p = 0.004), and liver (15.04 [2.96-76.35], p = 0.002) mortality risk compared with the no SLD group. This trend was more pronounced in the MetALD group with advanced fibrosis assessed by Fibrosis-4 (FIB-4). CONCLUSIONS: In individuals with CMRF, the presence of steatotic liver disease (MASLD) alone did not increase the risk of mortality, except in cases with more alcohol consumption (MetALD). Therefore controlling metabolic risk factors and reducing alcohol consumption in people with MASLD or MetALD will be crucial steps to improve long-term health outcomes.

Waitlist and transplant outcomes in patients with metabolic dysfunction-associated steatotic liver disease and autoimmune hepatitis.

BACKGROUND AND AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD), in the context of autoimmune hepatitis (AIH) among liver transplantation (LT) candidates or recipients remains poorly understood. This study compares waitlist and post-LT outcomes in patients with MASLD/AIH to MASLD and AIH alone. METHODS: Using the united network organ sharing database (2002-2022), we compared waitlist outcomes and post-LT survival among patients with MASLD/AIH (n = 282), AIH (n = 5812), and MASLD (n = 33 331). Competing risk, Kaplan Meier estimates and Cox proportional hazard analyses were performed. RESULTS: MASLD/AIH group had the highest rates of encephalopathy and ascites, and highest MELD scores. MASLD/AIH patients had higher transplantation incidence (adjusted subdistribution hazard ratio [aSHR] 1.64, 95% CI 1.44-1.85; p < .001) and lower waitlist removal risk (aSHR .30, 95% CI .20-.44; p < .001) compared to MASLD alone. One-year post-LT survival favoured MASLD compared to AIH (patient: 92% vs. 91%, p < .001; graft: 89% vs. 88%, p < .001) and MASLD/AIH (patient: 92% vs. 90%, p = .008; graft: 89% vs. 88%, p = .023). Recipients with MASLD/AIH showed no significant difference in survival at 10-year post-LT compared to MASLD (patient: 63% vs. 61%, p = .68; graft 60% vs. 59%, p = .83) and AIH (patient: 63% vs. 70%, p = .07; graft: 60% vs. 64%, p = .42). CONCLUSIONS: Our study showed that MASLD/AIH patients demonstrate higher LT incidence and lower dropout rates. Long-term post-LT outcomes did not significantly differ between groups. Further prospective multicenter studies are needed to validate these findings.

Waitlist and posttransplantation outcomes of lean individuals with nonalcoholic fatty liver disease.

Lean individuals with nonalcoholic fatty liver disease (NAFLD) represent a subset of patients with a distinct risk factor profile. We assessed the association between body mass index (BMI) on waitlist and postliver transplantation (LT) outcomes among these patients. We retrospectively analyzed the United Network for Organ Sharing data, including adult patients with NAFLD listed for LT between February 27, 2002, and June 30, 2020. We first used competing risk analyses to estimate the association of BMI with waitlist removal due to death or clinical deterioration. We then conducted Kaplan-Meier estimates and Cox regression models to determine the impact of weight change during the waiting list on all-cause mortality and graft failure after LT. Patients with normal weight (BMI 18.5-24.9 kg/m 2 ) suffered higher waitlist removal (adjusted subdistribution hazard ratio 1.26, 95% confidence interval [CI] 1.10-1.43; p = 0.001) compared with patients with obesity class I (BMI 30-34.9 kg/m 2 ). Those who remained at normal weight had higher all-cause mortality (adjusted hazard ratio [aHR] 1.61, 95% CI 1.32-1.96; p <0.001) and graft failure (aHR 1.57, 95% CI 1.32-1.88; p <0.001) than patients with stable obesity. Among patients with normal weight, those with the greatest weight increase (BMI gain ≥3 kg/m 2 ) had lower all-cause mortality (aHR 0.55, 95% CI 0.33-0.93; p = 0.03) and graft failure (aHR 0.49, 95% CI 0.30-0.81; p = 0.01) compared with patients with stable weight (BMI change ≤1 kg/m 2 ). Patients with NAFLD with normal weight have increased waitlist removal and those who remained at normal weight during the waitlist period have worse posttransplantation outcomes. Identifying and addressing factors influencing apparent healthy weight prior to LT are crucial to mitigate poor outcomes.

Pharmacological Therapy of Pruritus in Primary Biliary Cholangitis: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.

GOALS: We aim to summarize the current management of pruritus in primary biliary cholangitis (PBC) by evaluating the efficacy and safety of pharmacological therapies. BACKGROUND: Pruritus is a common symptom of PBC, and evidence regarding the most effective antipruritic agents available is lacking. New pharmacotherapy for PBC has shown promising antipruritic effects. STUDY: We performed a systematic literature review and meta-analysis including all available double-blind, randomized, placebo-controlled clinical trials that evaluated the efficacy of pharmacotherapy for the symptomatic management of pruritus in PBC. Pruritus was assessed as either a change from baseline or a postintervention score. RESULTS: We included 33 studies and 20 medications. Using the visual analog scale, cholestyramine did not significantly improve pruritus compared with placebo [standardized mean differences (SMD): -0.94, 95% CI: -2.05 to 0.17], whereas rifampin and nalfurafine hydrochloride both significantly improved pruritus (SMD: -3.29, 95% CI: -5.78 to -0.80; n=23 and SMD: -0.58, 95% CI: -1.04 to -0.12). In addition, Bezafibrate and linerixibat significantly improved pruritus (SMD: -1.05, 95% CI: -1.41 to -0.68; n=110 and SMD: -0.31, 95% CI: -0.62 to -0.04, respectively). This effect was also present within the subgroup analysis by pruritus scale, where both bezafibrate and linerixibat significantly improved pruritus compared with placebo (SMD: -1.09, 95% CI: -1.54 to -0.65; P <0.001; visual analog scale; as postintervention score and SMD: -0.31, 95% CI: -0.62 to -0.01; P =0.04; numeric rating scale; as a change from baseline score, respectively). CONCLUSIONS: Bezafibrate and Linerixibat are potential second-line antipruritic medications for PBC, particularly those with moderate to severe pruritus.

Steroid Use and Risk of Nonalcoholic Fatty Liver Disease in Patients With Inflammatory Bowel Disease: Systematic Review and Meta-analysis.

GOALS: We sought to evaluate the association of steroids with nonalcoholic fatty liver disease (NAFLD) among patients with inflammatory bowel disease (IBD). BACKGROUND: Patients with IBD are at increased risk of NAFLD. Steroids may have a role in the pathogenesis of NAFLD. STUDY: We searched MEDLINE (through PubMed) and Embase for studies from inception to July 2021. We included published interventional and observational studies of adults 18 years or older with ulcerative colitis or Crohn's disease. We reported odds ratios, 95% confidence intervals, and generated forest plots. A random effects model generated a summary effect estimate. Publication bias was assessed by funnel plot and Egger's test. Study quality was examined using modified Newcastle-Ottawa scale (NOS) and Agency for Healthcare Research and Quality (AHRQ). RESULTS: A total of 12 observational studies with 3497 participants were included. NAFLD was identified in 1017 (29.1%) patients. The pooled odds ratio for the development of NAFLD in steroid users versus non-users was 0.87 (95% confidence interval: 0.72-1.04). There was no significant heterogeneity between studies ( I ²=0.00%, P =0.13). No publication bias was detected by funnel plot or Egger's test ( P =0.24). Findings were consistent among subgroup analyses stratified by study quality. CONCLUSION: In this meta-analysis, steroids were not associated with NAFLD in patients with IBD. Steroids may not need to be withheld from patients with IBD for the purposes of preventing NAFLD. Additional prospective studies that systematically document steroid exposure and important confounders among patients with IBD are warranted.

Type 2 diabetes complications are associated with liver fibrosis independent of hemoglobin A1c.

INTRODUCTION AND OBJECTIVES: The association between type 2 diabetes, non-alcoholic fatty liver disease, and liver fibrosis is well established, but it is unknown whether complications of type 2 diabetes influence fibrosis levels. We defined the complications of type 2 diabetes by the presence of diabetic nephropathy, retinopathy, or neuropathy and aimed to evaluate their association with the degree of liver fibrosis measured by the fibrosis-4 (FIB-4) index. MATERIALS AND METHODS: This is a cross-sectional study evaluating the association of type 2 diabetes complications with liver fibrosis. A total of 2389 participants were evaluated from a primary care practice. FIB-4 was evaluated as a continuous and categorical measure using linear and ordinal logistic regression. RESULTS: Patients with complications were older, had higher hemoglobin A1c, and a higher median FIB-4 score (1.34 vs. 1.12, P<0.001). On adjusted analysis, type 2 diabetes complications were associated with higher fibrosis by continuous FIB-4 score (Beta-coefficient: 0.23, 95% confidence interval [CI]: 0.004-1.65) and demonstrated increased odds of fibrosis by categorical FIB-4 score (odds ratio [OR]: 4.48, 95% CI: 1.7-11.8, P=0.003), independent of hemoglobin A1c level. CONCLUSIONS: The presence of type 2 diabetes complications is associated with the degree of liver fibrosis, independent of hemoglobin A1c level.

Severe Hepatic Steatosis by Controlled Attenuation Parameter Predicts Quality of Life Independent of Fibrosis.

BACKGROUND & AIM: Liver fibrosis is associated with poor patient-reported outcomes (PROs), but the impact of steatosis is unknown. We aimed to evaluate the impact of steatosis on PROs independent of liver fibrosis. METHODS: We evaluated the impact of steatosis, measured by Controlled-Attenuation Parameter (CAP) on transient elastography, and PROs using the 2017-2018 National Health and Nutrition Examination Survey (NHANES) database. We used univariate and multivariate logistic and ordinal regression to evaluate categorical CAP score with PROs measuring physical disability, general health and depression. RESULTS: Of 4,509 participants included, 38% had severe steatosis (> 280 dB/m). Those with severe steatosis were older and more likely to be male (56% vs. 43% and 51%). On univariate analysis, severe steatosis was associated with more difficulty walking (P = 0.01), dressing (P = 0.005), lifting objects (P = 0.02), bending (P < 0.001), and moving large objects (P = 0.0006). After multivariate adjustment, severe steatosis remained associated with difficulty lifting objects (odds ratio [OR]: 1.7, 95% confidence interval [CI]: 1.2-2.4, P = 0.01) and difficulty bending (OR: 1.8, 95% CI: 1.2-2.7, P = 0.006). Severe steatosis increased risk of having any of the disabilities (OR: 1.7, 95% CI: 1.2-2.4, P = 0.008) and had higher ordinal disability index (OR: 1.6, 95% CI: 1.2-2.2, P = 0.007). Lastly, severe steatosis was also associated with worse self-perceived health status (OR: 1.5, 95% CI: 1.2-1.9, P = 0.002), while general health compared to one year ago and depression trended toward significance. CONCLUSION: Patients with severe steatosis are at increased risk of physical disability and have worse self-perceived health status independent of liver fibrosis.

Associations between alcohol consumption and hepatic steatosis in the USA.

Despite being widely recognized as a common cause of fatty liver, the exact impact of alcohol consumption on hepatic steatosis in the general population is elusive. The recent National Health and Nutrition Examination Survey (NHANES) allowed us to examine this relationship among US adults. Herein, we extracted data on detailed alcohol consumption and controlled attenuation parameter (CAP) by FibroScan from 4509 participants in NHANES 2017-2018. Compared to metabolic risk factors such as diabetes and obesity, the association between alcohol consumption and CAP was less significant. In multivariable analysis, only those drinking 5-7 times per week showed significant increases in CAP scores. Although both frequency and quantity of drinking were positively associated with CAP score, only frequency remained significant after adjustment for quantity and binge drinking. These epidemiological observations suggested that the impact of alcohol on hepatic steatosis was much smaller than metabolic factors and dependent upon the frequency of drinking.

Pregnancy in Chronic Liver Disease: Before and After Transplantation.

Chronic liver disease poses various challenges for women of reproductive age. Cirrhosis, particularly if decompensated, and liver transplantation may impact gestation and perinatal outcomes. Tailored management of underlying liver disease is critical to optimize maternal and fetal wellbeing. Early education, timely intervention, close monitoring, and a multidisciplinary approach are key elements required to minimize complications and increase chances of a safe and successful pregnancy. In this review, we focus on the pregnancy-related implications of chronic liver disease and liver transplantation on women of reproductive age and highlight disease-specific management considerations.

The presence of diabetes impacts liver fibrosis and steatosis by transient elastography in a primary care population.

INTRODUCTION AND OBJECTIVES: Noninvasive liver assessment in type 2 diabetes (T2DM) in a primary care population identifies higher risk non-alcoholic fatty liver disease (NAFLD). We aimed to evaluate the association of T2DM with liver fibrosis and steatosis by transient elastography (TE). MATERIALS AND METHODS: This is a retrospective study of a TE referral program where primary care physicians were able to order TE. Patients with alcohol abuse were excluded. TE and Controlled Attenuation Parameter (CAP) scores were obtained. Multivariable linear and logistic regression models were used to adjust for confounders. RESULTS: 28% had T2DM. The mean TE score in T2DM patients was 8.3 (±6) kilopascal (kPa) and 6.4 (±3.7) kPa in those without T2DM (p = 0.0001). Those with T2DM had a higher CAP (322 ± 51 dB/m vs. 296 ± 57 dB/m, p < 0.0001). In multivariable analysis, T2DM was associated with TE score (ß: 1.9, 95% confidence interval [CI]: 0.74-3.1, p = 0.001) and CAP (ß: 2.8, 95% CI: 9.3-36.2, p = 0.001). Patients with T2DM had higher-risk TE scores and more steatosis by CAP. CONCLUSION: T2DM is associated with liver fibrosis and steatosis by TE within a primary care population. A TE referral pathway may be utilized for T2DM patients who are at higher risk of NAFLD and its complications.

Long-term outcomes after liver transplantation in the Hispanic population.

BACKGROUND & AIMS: Racial/ethnic disparities in liver transplantation (LT) are well-recognized. Although Hispanics represent the largest and youngest minority group in the United States, limited data exist on long-term outcomes. We aimed to investigate long-term post-liver transplant outcomes in Hispanic patients and identify potential disparities compared to a baseline demographic of non-Hispanic white patients. METHODS: We performed a retrospective cohort study of first-time liver transplant recipients using the United Network for Organ Sharing database from 2002 to 2013, with follow-up through 2018. The primary outcomes of interest were overall patient and graft survival after LT. RESULTS: 45 767 patients underwent LT (85.0% non-Hispanic white, 15.0% Hispanic). Hispanics had lower socioeconomic status, higher prevalence of pretransplant comorbidities and more severe liver disease compared to non-Hispanic whites. Hispanics had similar patient (76.6% vs 75.6%; P = .12) and graft (71.7% vs 70.8%; P = .28) survival at 5 years and significantly better patient (62.9% vs 59.7%; P < .001) and graft (58.6% vs 55.6%; P = .002) survival at 10 years. In multivariable analysis, Hispanics had lower associated all-cause mortality (HR 0.86, 95% CI, 0.82-0.91; P < .001) and graft failure (HR 0.89, 95% CI, 0.85-0.93; P < .001) compared to non-Hispanic whites. In etiology-specific subanalysis, Hispanics transplanted for ALD, NASH and HCV had lower all-cause mortality compared to non-Hispanic whites. CONCLUSIONS: Hispanics have similar or better long-term post-LT outcomes compared to non-Hispanic whites despite a worse pretransplant risk factor profile. Further research is needed to clarify if this survival advantage reflects uncaptured protective factors or more stringent transplant selection in the Hispanic population.

Bone Health in Patients With Liver Diseases.

Osteoporosis is the most common bone disease in chronic liver disease (CLD) resulting in frequent fractures and leading to significant morbidity in this population. In addition to patients with cirrhosis and chronic cholestasis, patients with CLD from other etiologies may be affected in the absence of cirrhosis. The mechanism of osteoporosis in CLD varies according to etiology, but in cirrhosis and cholestatic liver disease it is driven primarily by decreased bone formation, which differs from the increased bone resorption seen in postmenopausal osteoporosis. Direct toxic effects from iron and alcohol play a role in hemochromatosis and alcoholic liver disease, respectively. Chronic inflammation also has been proposed to mediate bone disease in viral hepatitis and nonalcoholic fatty liver disease. Treatment trials specific to osteoporosis in CLD are small, confined to primary biliary cholangitis and post-transplant patients, and have not consistently demonstrated a benefit in this population. As it stands, prevention of osteoporosis in CLD relies on the mitigation of risk factors such as smoking and alcohol use, treatment of underlying hypogonadism, and encouraging a healthy diet and weight-bearing exercise. The primary medical intervention for the treatment of osteoporosis in CLD remains bisphosphonates though a benefit in terms of fracture reduction has never been shown. This review outlines what is known regarding the pathogenesis of bone disease in CLD and summarizes current and emerging therapies.

The Pharmacologic Management of Osteoporosis in Primary Biliary Cholangitis: A Systematic Review and Meta-Analysis.

INTRODUCTION: Osteoporosis is a common complication of primary biliary cholangitis (PBC) yet evidence for effective therapy is lacking. We sought to review all randomized controlled trials evaluating pharmacotherapy against placebo or no intervention for treatment of osteoporosis in PBC. METHODOLOGY: A comprehensive database search was conducted from inception through 29 March 2017. The primary outcome was incidence of fractures; secondary outcomes were change in bone mineral density (BMD) and adverse events. We assessed studies for risk of bias, graded quality of evidence, and used meta-analysis to obtain overall effect by pooling studies of the same drug class. RESULTS: We identified 11 randomized controlled trials evaluating bisphosphonates (3), hormone replacement therapy (2), ursodeoxycholic acid (1), obeticholic acid (1), cyclosporin A (1), vitamin K (1), calcitriol (1), and sodium fluoride (1). No intervention significantly reduced fractures compared to control. Although significant improvement in BMD was seen in one study with alendronate, a third-generation bisphosphonate, no significant improvement was seen on pooled analysis of all bisphosphonates including first-generation bisphosphonates (standard mean difference 0.41, p = 0.68). On pooled analysis, hormone replacement therapy modestly improved lumbar BMD (standard mean difference 0.69, p = 0.02), but with significantly increased adverse events (odds ratio 8.82, p = 0.01). CONCLUSIONS: There is a lack of high-quality evidence supporting the efficacy of any treatment of osteoporosis in PBC. This may be explained by lack of power in the included studies. However, our current understanding of PBC-related osteoporosis indicates that it results from decreased bone formation, which may explain the attenuated effect of traditional antiresorptive agents. Future studies should investigate newer anabolic bone agents.

Treatment of Fatigue in Primary Biliary Cholangitis: A Systematic Review and Meta-Analysis.

BACKGROUND AND AIMS: Fatigue is the most common complication of primary biliary cholangitis (PBC) and can be debilitating. Numerous interventions have been trialed targeting several proposed mechanisms of PBC-associated fatigue. We sought to summarize and perform a meta-analysis to determine the efficacy of these interventions. METHODS: A comprehensive database search was conducted from inception through March 27, 2018. The primary outcome was proportion of fatigued patients or reduction in degree of fatigue. Adverse events were a secondary outcome. We assessed studies for risk of bias, graded quality of evidence, and used meta-analysis to obtain overall effect by pooling studies of the same class. RESULTS: We identified 16 studies evaluating ursodeoxycholic acid (UDCA) (7), liver transplantation (2), serotonin reuptake inhibitors (2), colchicine (1), methotrexate (1), cyclosporine (1), modafinil (1), and obeticholic acid (1). On meta-analysis, UDCA was not associated with a reduction in risk of fatigue (RR = 0.86, 95% CI 0.69-1.08, p = 0.19, I2 = 56.2%). While liver transplantation did reduce degree of fatigue (SMD - 0.57, 95% CI - 0.89 to - 0.24, p = 0.001, I2 = 67.3%), fatigue did not return to baseline indicating the underlying cause may not be addressed. CONCLUSIONS: While there is some improvement in fatigue with liver transplantation, there is a lack of high-quality evidence supporting the efficacy of any other intervention in the treatment of PBC-related fatigue. Further research into the underlying pathophysiology may help guide future trials.

Ethnicity Influences Phenotype and Outcomes in Inflammatory Bowel Disease: A Systematic Review and Meta-analysis of Population-based Studies.

BACKGROUND & AIMS: Inflammatory bowel diseases (IBDs) (Crohn's disease [CD], ulcerative colitis) are global diseases. Similarities and differences in disease presentation and outcomes across different geographic regions and ethnic groups have not been compared previously. METHODS: We performed a systematic review and meta-analysis of population-based cohort studies examining the phenotype and outcome of IBD across ethnic groups categorized as Whites, Blacks, Hispanics, and Asians. Further stratification was performed by migration status (native or immigrant). Pooled proportions of disease location, behavior, medication, and surgery use were calculated by using a random-effects model and compared statistically. RESULTS: Our final analysis included 198 unique studies reporting outcomes on 525,425 IBD patients (Caucasian, 65%; Asian, 30%; Hispanic, 2%; and Black, 1%). CD in Asians but not other ethnicities demonstrated a strong male predominance. Family history of IBD was infrequent in Asian patients. Both Black and Asian CD patients demonstrated perianal involvement more frequently. Surgery for both CD and UC was less common in Asians than Caucasians. Compared with native residents, a family history of IBD was reported more often among immigrant IBD patients, but no significant differences were noted in phenotype. CONCLUSIONS: We demonstrate significant variation in the demographic distribution, familial predisposition, phenotype, and outcomes of IBD between Caucasians, Blacks, Hispanics, and Asians. There is need for further study to understand the biology behind this variation.