Liver surface nodularity and ascites are associated with mortality risk in acute alcohol-associated hepatitis.

BACKGROUND: Acute alcohol-associated hepatitis (AH) is associated with high mortality. CT-derived liver surface nodularity (LSN) is a robust prognostic biomarker in other chronic liver diseases. The aim of this study was to determine relationships between LSN, disease severity, and mortality in AH. METHODS: Adults hospitalized with AH from January 2016 to March 2020 were included if an abdominal CT was performed between 8 weeks prior to 72 h after hospitalization. LSN was measured using quantitative methods (Liver Surface Nodularity Software version 0.88, Birmingham, AL, USA). Cox proportional hazards models, logistic regression and AUROC analysis were used to examine relationships between LSN and 180-day transplant-free survival. RESULTS: Of 386 patients hospitalized with AH during the study period, 230 had CT scans performed, and 205 met inclusion criteria. Mean transplant-free survival was 127 days (95% CI 118-137). Within each cohort, patients were grouped into low [LSN-LOW, N = 109 (53.2%)] and high [LSN-HIGH, N = 96 (46.8%)] LSN strata based on an optimal cutoff of 2.86 derived from unadjusted ROC curves. Patients with high LSN had features of portal hypertension, which included encephalopathy [53 (55.2%) vs. 43 (39.4%), p = 0.017], ascites on CT [81 (84.4%) vs. 69 (63.3%), p = 0.001] and portosystemic shunts [78 (81.2%) vs. 69 (63.3%), p = 0.003]. High LSN, ascites and MELD were independently associated with lower likelihood of 180-day transplant-free survival, and inclusion of a score assigning 1 point each for high LSN or ascites on CT (AHRADS score) to MELD enhanced diagnostic accuracy of AUROC for 180-day survival compared to MELD alone [AUROC 0.782 (95% CI 0.719-0.845) vs. 0.735 (0.667-0.802), p = 0.023]. CONCLUSIONS: CT-derived factors that include LSN and ascites are radiographic biomarkers associated with 180-day transplant-free survival in alcohol-associated hepatitis.

A novel scoring system to predict survival in cirrhotic patients undergoing isolated lung transplantation: The PENS-CEPT score.

Cirrhosis is usually regarded as a contraindication to isolated lung transplantation (ILT). We sought to determine which patients with cirrhosis could safely undergo ILT. Based on a retrospective analysis of patients with cirrhosis who underwent ILT at our center between 2007 and 2020, we developed an exclusionary algorithm (PENS-CEPT: Pittsburgh ExclusioN Score in Cirrhotics Evaluated for Pulmonary Transplant) to help determine which patients can undergo ILT with minimal incurred risk from their underlying liver disease. The score utilizes a combination of readily available clinical data and the presence (or absence) of spontaneous portosystemic shunts on preoperative cross-sectional imaging. Sixteen patients underwent ILT with a diagnosis of cirrhosis: nine with cystic fibrosis. On univariate analysis, only our model was able to predict 1 year survival. Of the nine patients that would have been approved using our model, there was only one short term death. Of the seven patients that would have been rejected by the model, all but one died within the first year with six dying of complications from liver failure. We are proposing a simple score utilizing routine clinical parameters and pre-operative imaging to determine the safety of ILT in cirrhotic patients. Further studies are required to validate this scoring system with the goal of safely increasing the opportunity for cirrhotic patients who would otherwise be rejected for ILT.

Prevalence and clinical impact of alcohol withdrawal syndrome in alcohol-associated hepatitis and the potential role of prophylaxis: a multinational, retrospective cohort study.

Background: The prevalence and impact of alcohol withdrawal syndrome (AWS) in patients with alcohol-associated hepatitis (AH) are unknown. In this study, we aimed to investigate the prevalence, predictors, management, and clinical impact of AWS in patients hospitalized with AH. Methods: A multinational, retrospective cohort study enrolling patients hospitalized with AH at 5 medical centres in Spain and in the USA was performed between January 1st, 2016 to January 31st, 2021. Data were retrospectively retrieved from electronic health records. Diagnosis of AWS was based on clinical criteria and use of sedatives to control AWS symptoms. The primary outcome was mortality. Multivariable models controlling for demographic variables and disease severity were performed to determine predictors of AWS (adjusted odds ratio [OR]) and the impact of AWS condition and management on clinical outcomes (adjusted hazard ratio [HR]). Findings: In total, 432 patients were included. The median MELD score at admission was 21.9 (18.3-27.3). The overall prevalence of AWS was 32%. Lower platelet levels (OR = 1.61, 95% CI 1.05-2.48) and previous history of AWS (OR = 2.09, 95% CI 1.31-3.33) were associated with a higher rate of incident AWS, whereas the use of prophylaxis decreased the risk (OR = 0.58, 95% CI 0.36-0.93). The use of intravenous benzodiazepines (HR = 2.18, 95% CI 1.02-4.64) and phenobarbital (HR = 2.99, 95% CI 1.07-8.37) for AWS treatment were independently associated with a higher mortality. The development of AWS increased the rate of infections (OR = 2.24, 95% CI 1.44-3.49), the need for mechanical ventilation (OR = 2.49, 95% CI 1.38-4.49), and ICU admission (OR = 1.96, 95% CI 1.19-3.23). Finally, AWS was associated with higher 28-day (HR = 2.31, 95% CI 1.40-3.82), 90-day (HR = 1.78, 95% CI 1.18-2.69), and 180-day mortality (HR = 1.54, 95% CI 1.06-2.24). Interpretation: AWS commonly occurs in patients hospitalized with AH and complicates the hospitalization course. Routine prophylaxis is associated with a lower prevalence of AWS. Prospective studies should determine diagnostic criteria and prophylaxis regimens for AWS management in patients with AH. Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Portal vein thrombosis and renal dysfunction: a national comparative study of liver transplant recipients for NAFLD versus alcoholic cirrhosis.

The prevalence of portal vein thrombosis (PVT), renal dysfunction (RD), and simultaneous PVT/RD in liver transplantation (LT) is poorly understood. We analyzed the prevalence of PVT, RD, simultaneous PVT/RD, and the outcomes of adult recipients of LT for nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) between 2006 and 2016 in the United States. We found that the prevalence of PVT (7.2% â†’ 11.3%), RD (33.8% â†’ 39.2%), and simultaneous PVT/RD (2.4% â†’ 4.5%) has increased significantly over the study period (all P-values <0.05). NAFLD patients had a higher proportion of PVT (14.8% vs. 9.2%), RD (45.0% vs. 42.1%), and simultaneous PVT/RD (6.5% vs. 3.9%; all P-values <0.05). 90-day mortality was 3.8%, 6.3%, 6.8%, and 9.8% for PVT(-)/RD(-), PVT(-)/RD(+), PVT(+)/RD(-), and PVT(+)/RD(+) recipients, respectively (P < 0.01). 5-year survival was 82.1%, 75.5%, 74.8%, and 71.1% for PVT(-)/RD(-), PVT(-)/RD(+), PVT(+)/RD(-), and PVT(+)/RD(+) recipients, respectively (P < 0.05). In conclusion, the prevalence of PVT, RD, and simultaneous PVT/RD has increased among LT recipients, especially for those with NAFLD. The short- and long-term outcomes of recipients with PVT, RD, and simultaneous PVT/RD were inferior to patients without those risk factors irrespective of their indication for LT. No differences in patient outcomes were found between ALD and NAFLD recipients after stratification by risk factors.

The liver transplant risk score prognosticates the outcomes of liver transplant recipients at listing.

BACKGROUND: We assessed if the risk of post-liver transplant mortality within 24 h could be stratified at the time of listing using the liver transplant risk score (LTRS). Secondary aims were to assess if the LTRS could stratify the risk of 30-day, 1-year mortality, and survival beyond the first year. METHODS: MELD, BMI, age, diabetes, and the need for dialysis were the five variables used to calculate the LTRS during patients' evaluation for liver transplantation. Mortality rates at 24 h, 30 days, and 1-year were compared among groups of patients with different LTRS. Patients with ABO-incompatibility, redo, multivisceral, partial graft and malignancies except for hepatocellular carcinoma were excluded. Data of 48,616 adult liver transplant recipients were extracted from the Scientific Registry of Transplant Recipients between 2002 and 2017. RESULTS: 24-h mortality was 0.9%, 1.0%, 1.1%, 1.7%, 2.3%, 2.0% and 3.5% for patients with LTRS of 0,1,2,3,4, 5 and ≥ 6, respectively (P < 0.001). 30-day mortality was 3.5%, 4.2%, 4.9%, 6.2%, 7.6%, 7.2% and 10.1% respectively (P < 0.001). 1-year mortality was 8.6%, 10.8%, 12.9%, 13.9%, 18.5%, 20.3% and 28.6% respectively (P < 0.001). 10-year survival was 61%, 56%, 57%, 54%, 47%, and 31% for patients with 0, 1, 2, 3, 4, 5 and ≥ 6 points respectively (P < 0.001). CONCLUSION: Perioperative mortality and long-term survival of patients undergoing LT can be accurately estimated at the time of listing by the LTRS.

Alcoholic-related liver disease: pathogenesis, management and future therapeutic developments

Alcohol-related liver disease (ALD) is the most frequent cause of advanced chronic liver disease worldwide. Excessive and prolonged alcohol use leads to ALD, which ranges from early forms such as alcoholic fatty liver (AFL) and alcoholic steatohepatitis (ASH), through progressive fibrosis to cirrhosis and the development of hepatocellular cancer (HCC). In addition, patients with underlying ALD and continuous alcohol use can develop alcoholic hepatitis (AH), which presents a rapid progression of liver failure and has a high short-term mortality. Genetic, environmental and epigenetic factors influence the progression of ALD to more severe forms. The pathogenesis of ALD is complex and involves multiple pathways. Recent translational studies have demonstrated a key role of the gut-liver axis and innate immunity in hepatocellular damage and fibrosis. In severe forms, hepatocellular de-differentiation and systemic inflammation contribute to liver failure and multiorgan failure. Alcohol abstinence is the cornerstone of therapy for ALD and the prevention of its complications, but the efficacy and accessibility of psycho-familial-social interventions is still poor and effective public health policies to limit problematic alcohol use need to be implemented. Prednisolone is the only current option for AH, with a transient beneficial effect over placebo. For patients with decompensated ALD-cirrhosis and/or development of HCC, liver transplantation (LT) may be required. In recent years, early LT is being increasingly offered to carefully selected AH patients, with excellent long-term survival. New trials of AH treatments are currently ongoing, and translational studies in human samples are paving the way to new promising targeted therapies

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Differential Outcomes and Clinical Challenges of NAFLD With Extreme Obesity.

Nonalcoholic fatty liver disease (NAFLD) is closely associated with obesity. The prevalence of extreme obesity, defined as body mass index (BMI) of 50 kg/m2 or higher, is rising more rapidly than overall obesity. We aimed to compare the clinical outcomes and performance of noninvasive fibrosis assessment tools in NAFLD with or without extreme obesity. A retrospective analysis was performed in 304 patients with NAFLD with extreme obesity and compared them to patients with NAFLD with BMI of 40 kg/m2 or less, matched for age, gender, race, and liver fibrosis stage. The mean age of the NAFLD with extreme obesity cohort was 55.9 years, BMI 55 kg/m2, and 49.7% had cirrhosis at initial evaluation. Baseline cirrhosis and coronary artery disease were associated with increased risk of death, and dyslipidemia with decreased risk of mortality. Age, insulin use, hypertension, albumin and platelet count were associated with cirrhosis. Fifteen percent of patients had weight-loss surgery, but this was not associated with survival or risk of cirrhosis. Of the 850 abdominal ultrasound scans performed in 255 patients, 24.1% were deemed suboptimal for hepatocellular carcinoma screening. The mean NAFLD fibrosis score (NFS) in the extreme obesity cohort, versus a propensity-matched cohort with BMI of 40 kg/m2 or less, was significantly different for both low fibrosis (F0-F2) (0.222 vs. -1.682, P < 0.0001) and high fibrosis (F3-F4) (2.216 vs. 0.557, P < 0.001). Conclusion: NAFLD with extreme obesity is associated with increased risk of liver-related and overall mortality. Accurate noninvasive assessment of liver fibrosis, low rates of weight loss surgery, and high failure rate of ultrasound were identified as clinical challenges in this population.

Alcoholic-related liver disease: pathogenesis, management and future therapeutic developments.

Alcohol-related liver disease (ALD) is the most frequent cause of advanced chronic liver disease worldwide. Excessive and prolonged alcohol use leads to ALD, which ranges from early forms such as alcoholic fatty liver (AFL) and alcoholic steatohepatitis (ASH), through progressive fibrosis to cirrhosis and the development of hepatocellular cancer (HCC). In addition, patients with underlying ALD and continuous alcohol use can develop alcoholic hepatitis (AH), which presents a rapid progression of liver failure and has a high short-term mortality. Genetic, environmental and epigenetic factors influence the progression of ALD to more severe forms. The pathogenesis of ALD is complex and involves multiple pathways. Recent translational studies have demonstrated a key role of the gut-liver axis and innate immunity in hepatocellular damage and fibrosis. In severe forms, hepatocellular de-differentiation and systemic inflammation contribute to liver failure and multiorgan failure. Alcohol abstinence is the cornerstone of therapy for ALD and the prevention of its complications, but the efficacy and accessibility of psycho-familial-social interventions is still poor and effective public health policies to limit problematic alcohol use need to be implemented. Prednisolone is the only current option for AH, with a transient beneficial effect over placebo. For patients with decompensated ALD-cirrhosis and/or development of HCC, liver transplantation (LT) may be required. In recent years, early LT is being increasingly offered to carefully selected AH patients, with excellent long-term survival. New trials of AH treatments are currently ongoing, and translational studies in human samples are paving the way to new promising targeted therapies.

Recent advances in alcoholic hepatitis.

Alcoholic hepatitis is the severest clinical presentation of alcoholic liver disease. Lacking an effective pharmacologic treatment, alcoholic hepatitis is associated with a poor prognosis and its recovery relies mostly on abstinence. With alcohol use disorder being universally on the rise, the impact of alcoholic hepatitis on society and health-care costs is expected to increase significantly. Prognostic factors and liver biopsy can help with timely diagnosis, to determine eligibility and response to corticosteroids, and for prognostication and transplant referral. Although recent discoveries in the pathophysiology of alcoholic hepatitis are encouraging and could pave the way for novel treatment modalities, a multidisciplinary approach considering timely identification and treatment of liver-related complications, infectious and metabolic disease, malnutrition, and addiction counseling should be emphasized. Apart from proper selection of candidates, transplant programs should provide adequate post-transplant addiction support in order to make of early liver transplantation for alcoholic hepatitis the ultimate sobering experience in the next decade.

Liver stiffness measurement in patients with nodular regenerative hyperplasia undergoing magnetic resonance elastography.

PURPOSE: Nodular regenerative hyperplasia (NRH) may mimic cirrhosis at imaging. We aim to investigate the effect of NRH on liver stiffness measurement (LSM) obtained with magnetic resonance elastography (MRE). METHODS: This retrospective, Institutional Review Board-approved study included 37 subjects with NRH (Group 1) and no or minimal fibrosis (F0-F1), a control group (Group 2) made of 30 subjects with non-advanced fibrosis (F0-F2), and a control group (Group 3) made of 30 subjects with advanced fibrosis (F3-F4), all with available MRE. LSM was measured in each subject along with assessment of hepatic morphological features of cirrhosis and signs of portal hypertension. The significance of the difference in mean LSM between Group 1 and 2 and between Group 1 and 3 was evaluated using the Mann-Whitney U test. The difference in distribution of imaging features among groups was assessed using the Pearson χ2 or Fisher exact test. RESULTS: The mean ± SD LSM in Group 1 (3.56 ± 1.10 kPa) was significantly higher compared to Group 2 (2.91 ± 0.52 kPa, P = 0.019) and significantly lower compared to Group 3 (7.18 ± 2.08 kPa, P < 0.001). Twelve (32%) patients with NRH had LSM ≥ 4.11 kPa, and 6 (16%) patients had LSM ≥ 4.71 kPa. Surface nodularity (P = 0.032) and caudate lobe hypertrophy (P = 0.004) were more commonly visualized in Group 1 than in Group 2. At least one feature of portal hypertension was observed in 16 (43%) NRH subjects. CONCLUSION: NRH may increase the LSM obtained with MRE and may represent a confounding factor when using liver stiffness for the non-invasive diagnosis of fibrosis.

The ZJU index is a powerful surrogate marker for NAFLD in severely obese North American women.

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the western world and is highly associated with multiple cardiometabolic complications. The Zhejiang University (ZJU) index was first developed to predict NAFLD in Chinese populations, where it was shown to have better predictive value than other currently used indices. The aims of the present study were to 1) determine the diagnostic accuracy of ZJU index in identifying NAFLD in a well-phenotyped cohort of obese middle-aged American women and 2) compare its performance with other non-invasive indices for NAFLD identification. METHODS: To achieve this goal, we performed a retrospective analysis of a prospectively-collected cohort of participants enrolled in a weight loss trial for severe obesity (RENEW, clinicaltrials.gov identifier: NCT00712127). One hundred and seven women between the age of 30 and 55 with obesity class II (BMI 35-39.9 kg/m2) or class III (BMI ≥ 40 kg/m2) were recruited for analyses. Hepatic steatosis was measured using liver/spleen attenuation ratio (L/S ratio) from unenhanced abdominal computed tomography. Beside ZJU index, hepatic steatosis index (HSI), lipid accumulation production index (LAPI), and visceral adiposity index (VAI) were also determined and to compare their performance in predicting NAFLD. RESULTS: Of 107 obese women in the study, 40 (37.4%) met imaging criteria for NAFLD using cut-off value of L/S ratio < 1.1. The ZJU index was positively correlated with HIS, LAPI, but not VAI. The area under the curve was highest for the ZJU index (AUC = 0.742, 95% CI:0.647-0.837), followed by HSI (AUC = 0.728, 95% CI:0.631-0.825), LAPI (AUC = 0.682, CI:0.583-0.781), and VAI (AUC = 0.621, 95% CI:0.518-0.725), respectively, using the Youden method. CONCLUSION: The ZJU index is a powerful surrogate marker for NAFLD in severely obese western females and its predictive value was better than that of other commonly used indices for predicting NAFLD. Our study is the first to suggest that the ZJU index could be a promising model for use in western as well as Chinese populations.

A Celiac Disease Phenotype After Checkpoint Inhibitor Exposure: An Example of Immune Dysregulation After Immunotherapy.

Celiac disease is characterized by duodenal inflammation after exposure to gluten. Checkpoint inhibitors are antibodies that inhibit the inhibitory signals of the cytotoxic T lymphocytes to enhance antitumor responses. A 79-year-old man with an unknown history of celiac disease underwent treatment with pembrolizumab for recurrent left maxillary melanoma. He subsequently developed diarrhea and weight loss. Serology was positive for anti-tissue transglutaminase immunoglobulin A. Upper endoscopy revealed duodenal villous atrophy, which was confirmed on biopsy. A gluten-free diet was not tolerated, and symptoms resolved with withdrawal of pembrolizumab and steroid administration for another medical reason.

Impact of Hepatic Steatosis on Resting Metabolic Rate and Metabolic Adaptation in Response to Intentional Weight Loss.

Weight loss is the primary intervention for nonalcoholic fatty liver disease (NAFLD). A decrease in resting metabolic rate (RMR) out of proportion to the degree of weight loss may promote weight regain. We aimed to determine the impact of hepatic steatosis on weight loss-associated changes in RMR and metabolic adaptation, defined as the difference between predicted and measured RMR after weight loss. We retrospectively analyzed prospectively collected data from 114 subjects without diabetes (52 with NAFLD), with body mass index (BMI) >35, and who enrolled in a 6-month weight loss intervention. Hepatic steatosis was determined by unenhanced computed tomography scans by liver:spleen attenuation ratio <1.1. RMR was measured by indirect calorimetry. At baseline, patients with hepatic steatosis had higher BMI, fat mass (FM), fat-free mass (FFM), and RMR (RMR, 1,933 kcal/day; 95% confidence interval [CI], 841-2,025 kcal/day; versus 1,696; 95% CI, 1,641-1,751; P < 0.0001). After 6 months, the NAFLD group experienced larger absolute declines in weight, FM, and FFM, but percentage changes in weight, FFM, and FM were similar between groups. A greater decline in RMR was observed in patients with NAFLD (-179 kcal/day; 95% CI, -233 to -126 kcal/day; versus -100; 95% CI, -51 to -150; P = 0.0154) for the time × group interaction, and patients with NAFLD experienced greater metabolic adaptation to weight loss (-97 kcal/day; 95% CI, -143 to -50 kcal/day; versus -31.7; 95% CI, -74 to 11; P = 0.0218) for the prediction × group interaction. The change (Δ) in RMR was significantly associated with ΔFM, ΔFFM, and baseline RMR, while metabolic adaptation was significantly associated with female sex and ΔFM only. Conclusion: Hepatic steatosis is associated with a greater reduction in FM, which predicts RMR decline and a higher metabolic adaptation after weight loss, potentially increasing the risk of long-term weight regain.

Reduced Serum Sphingolipids Constitute a Molecular Signature of Malnutrition in Hospitalized Patients With Decompensated Cirrhosis.

INTRODUCTION: Malnutrition is a leading cause of morbidity and mortality in cirrhosis. Although multiple noninvasive measures of nutritional status have been studied, no consensus exists for early identification of malnutrition in cirrhosis. Serum metabolomics offers a novel approach for identifying biomarkers in multiple disease states. To characterize alterations in metabolic pathways associated with malnutrition in hospitalized cirrhotic patients and to identify biomarkers for disease prognosis. METHODS: In this cross-sectional, observational cohort study, 51 hospitalized cirrhotic patients were classified as malnourished (42.3%) or nourished (57.7%) based on low mid-arm muscle circumference and dominant handgrip strength. Anthropometric measurements and computed tomography body composition analysis were performed. Serum was collected after overnight fasting for unbiased metabolomics analysis. RESULTS: Malnourished cirrhotic patients exhibited mild reductions in skeletal muscle index, with more marked reductions in visceral fat index. Seventy-one biochemicals were significantly altered in malnourished subjects. The serum metabolite profile was significantly different between nourished and malnourished cirrhotic patients. Pathway analysis demonstrated that only sphingolipid metabolic pathways were significantly enriched in altered metabolites. Hierarchical clustering revealed that sphingolipid metabolites clustered into nourished and malnourished cohorts. Spearman analysis demonstrated multiple statistically significant correlations between sphingolipid species and Model for End-Stage Liver Disease-Sodium. Using logistic regression, we identified 8 sphingolipids that were significantly associated with malnutrition after controlling for Model for End-Stage Liver Disease-Sodium, age, and gender. CONCLUSIONS: Malnutrition in hospitalized cirrhotic patients is characterized by reductions in multiple sphingolipid species. Dysregulated sphingolipid metabolism may be involved in the pathophysiology of malnutrition in cirrhosis and potentially serve as a biomarker of nutritional status in this population.

Targeting Cholinergic System to Modulate Liver Injury.

Over the past few decades, evidence accumulated to indicate that parasympathetic innervation regulates liver injury and regeneration. Liver derives its parasympathetic input via vagus nerve. In animal models, vagus nerve stimulation and transection are frequently used to determine the impact of parasympathetic input on liver injury responses. Such strategies provide limited understanding of postneuronal mechanisms involved in the regulation of liver injury. The hepatic branch of vagus nerve releases acetylcholine (ACh), which activates muscarinic and nicotinic receptors in hepatocytes as well as non-parenchymal cells to modulate cellular functions. Moreover, vagus nerve releases other neurotransmitters such as vasoactive intestinal peptide (VIP), which also modulates liver injury responses and hemodynamics. Therefore, our understanding of the post-neuronal modulation of liver injury in models utilizing vagus nerve activity remains limited. Gene-silencing technologies and pharmacological manipulation of receptor activity have not only improved our understanding of the role of specific cholinergic receptors but also elucidated the role of various liver cell sub-populations in modulating liver injury response. With advent of organ- and cell-specific transgenic mice, our understanding of neural regulation of liver injury is likely to improve further. This review comprehensively provides current understanding of cholinergic regulation of liver injury, and points to potential therapeutic targets to treat liver injury.

Differential Impact of Weight Loss on Nonalcoholic Fatty Liver Resolution in a North American Cohort with Obesity.

OBJECTIVE: Nonalcoholic fatty liver disease (NAFLD) is closely associated with obesity. In this study, a North American cohort with obesity enrolled in a lifestyle modification program was examined to determine the impact of weight loss on NAFLD resolution and sarcopenia. METHODS: Nondiabetic individuals with World Health Organization Class II/III obesity enrolled in a 6-month weight loss intervention were included. Steatosis was measured using computed tomography (CT)-derived liver:spleen attenuation ratio. Body composition was assessed using dual X-ray absorptiometry, air-displacement plethysmography, and CT anthropometry. RESULTS: At baseline, participants with NAFLD had greater visceral adipose tissue (VAT) but similar skeletal muscle area compared to those without NAFLD. After intervention, weight loss was similar in the two groups, but participants with NAFLD lost more VAT than those without NAFLD (-38.81 [-55.98 to -21.63] cm2 vs. -13.82 [-29.65 to -2.02] cm2 ; P = 0.017). In the subset with NAFLD at baseline, participants with NAFLD resolution after intervention lost more VAT than those with persistent NAFLD (-57.23 [-88.63 to -25.84) cm2 vs. -26.92 [-52.14 to -26.92] cm2 , P = 0.039). CONCLUSIONS: In a Western cohort with obesity, NAFLD was not associated with sarcopenia. After lifestyle modification, there was a differential impact on NAFLD resolution, with twofold greater VAT loss in participants who resolved NAFLD compared with those with persistent NAFLD despite similar weight loss.

Serum Leptin Is a Biomarker of Malnutrition in Decompensated Cirrhosis.

BACKGROUND AND AIMS: Malnutrition is a leading cause of morbidity and mortality in cirrhosis. There is no consensus as to the optimal approach for identifying malnutrition in end-stage liver disease. The aim of this study was to measure biochemical, serologic, hormonal, radiographic, and anthropometric features in a cohort of hospitalized cirrhotic patients to characterize biomarkers for identification of malnutrition. DESIGN: In this prospective observational cohort study, 52 hospitalized cirrhotic patients were classified as malnourished (42.3%) or nourished (57.7%) based on mid-arm muscle circumference < 23 cm and dominant handgrip strength < 30 kg. Anthropometric measurements were obtained. Appetite was assessed using the Simplified Nutrition Appetite Questionnaire (SNAQ) score. Fasting levels of serum adipokines, cytokines, and hormones were determined using Luminex assays. Logistic regression analysis was used to determine features independently associated with malnutrition. RESULTS: Subjects with and without malnutrition differed in several key features of metabolic phenotype including wet and dry BMI, skeletal muscle index, visceral fat index and HOMA-IR. Serum leptin levels were lower and INR was higher in malnourished subjects. Serum leptin was significantly correlated with HOMA-IR, wet and dry BMI, mid-arm muscle circumference, skeletal muscle index, and visceral fat index. Logistic regression analysis revealed that INR and log-transformed leptin were independently associated with malnutrition. CONCLUSIONS: Low serum leptin and elevated INR are associated with malnutrition in hospitalized patients with end-stage liver disease.

Frailty as Tested by Gait Speed is an Independent Risk Factor for Cirrhosis Complications that Require Hospitalization.

OBJECTIVES: Frailty is a known risk factor for major life-threatening liver transplant complications, deaths, and waitlist attrition. Whether frailty indicates risk for adverse outcomes in cirrhosis short of lethality is not well defined. We hypothesized that clinical measurements of frailty using gait speed and grip strength would indicate the risk of subsequent hospitalization for the complications of cirrhosis. METHODS: We assessed frailty as gait speed and grip strength in a 1-year prospective study of 373 cirrhotic patients evaluated for or awaiting liver transplantation. We determined its association with the outcome of subsequent hospital days/100 days at risk for 7 major complications of cirrhosis. We tested potential covariate influences of Model for Endstage Liver Disease (MELD) and Child-Turcotte-Pugh (CTP) scores, age, sex, height, depression, narcotic use, vitamin D deficiency, and hepatocellular carcinoma using multivariable modeling. RESULTS: Patients experienced 2.14 hospital days/100 days at risk, or 7.81 days/year. Frailty measured by gait speed was a strong risk factor for hospitalization for all cirrhosis complications. Each 0.1 m/s gait speed decrease was associated with 22% greater hospital days (P<0.001). Grip strength showed a similar but nonsignificant association. Gait speed remained independently significant when adjusted for MELD, CTP, and other covariates. At hospital costs of $4,000/day, patients with normal 1 m/s gait speed spent 6.2 days and $24,800/year; patients with 0.5 m/s speed spent 21.2 days and $84,800/year; and patients with 0.25 m/s speed spent 40.2 days and $160,800/year. CONCLUSIONS: Frailty as measured by gait speed is an independent and potentially modifiable risk factor for cirrhosis complications requiring hospitalization. The potential clinical value of frailty measurements to help define such risk merits broader evaluation.

M1 Muscarinic Receptor Deficiency Attenuates Azoxymethane-Induced Chronic Liver Injury in Mice.

Cholinergic nervous system regulates liver injury. However, the role of M1 muscarinic receptors (M1R) in modulating chronic liver injury is uncertain. To address this gap in knowledge we treated M1R-deficient and WT mice with azoxymethane (AOM) for six weeks and assessed liver injury responses 14 weeks after the last dose of AOM. Compared to AOM-treated WT mice, M1R-deficient mice had attenuated liver nodularity, fibrosis and ductular proliferation, α-SMA staining, and expression of α1 collagen, Tgfß-R, Pdgf-R, Mmp-2, Timp-1 and Timp-2. In hepatocytes, these findings were associated with reductions of cleaved caspase-3 staining and Tnf-α expression. In response to AOM treatment, M1R-deficient mice mounted a vigorous anti-oxidant response by upregulating Gclc and Nqo1 expression, and attenuating peroxynitrite generation. M1R-deficient mouse livers had increased expression of Trail-R2, a promotor of stellate cell apoptosis; dual staining for TUNNEL and α-SMA revealed increased stellate cells apoptosis in livers from M1R-deficient mice compared to those from WT. Finally, pharmacological inhibition of M1R reduced H2O2-induced hepatocyte apoptosis in vitro. These results indicate that following liver injury, anti-oxidant response in M1R-deficient mice attenuates hepatocyte apoptosis and reduces stellate cell activation, thereby diminishing fibrosis. Therefore, targeting M1R expression and activation in chronic liver injury may provide therapeutic benefit.

Assessing Myogenic Response and Vasoactivity In Resistance Mesenteric Arteries Using Pressure Myography.

Small resistance arteries constrict and dilate respectively in response to increased or decreased intraluminal pressure; this phenomenon known as myogenic response is a key regulator of local blood flow. In isobaric conditions small resistance arteries develop sustained constriction known as myogenic tone (MT), which is a major determinant of systemic vascular resistance (SVR). Hence, ex vivo pressurized preparations of small resistance arteries are major tools to study microvascular function in near-physiological states. To achieve this, a freshly isolated intact segment of a small resistance artery (diameter ~260 µm) is mounted onto two small glass cannulas and pressurized. These arterial preparations retain most in vivo characteristics and permit assessment of vascular tone in real-time. Here we provide a detailed protocol for assessing vasoactivity in pressurized small resistance mesenteric arteries from rats; these arteries develop sustained vasoconstriction - approximately 25% of maximal diameter - when pressurized at 70 mmHg. These arterial preparations may be used to study the effect of investigational compounds on relationship between intra-arterial pressure and vasoactivity and determine changes in microvascular function in animal models of various diseases.