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The prevalence of alcohol use disorder (AUD) has been steadily increasing over the past decade. In parallel, alcohol-associated liver disease (ALD) has been increasing at an alarming rate, especially among young patients. Data suggest that most patients with ALD do not receive AUD therapy. Although liver transplantation is the only curative therapy for end-stage ALD, transplant candidacy is often a matter of debate given concerns about patients being under-treated for AUD and fears of post-transplantation relapse affecting the allograft. In this Review, we discuss diagnosis, predictors and effects of relapse, behavioural therapies and pharmacotherapies, and we also propose an integrative, multidisciplinary and multimodality approach for treating AUD in patients with cirrhosis, especially in the setting of liver transplantation. Notably, this approach takes into account the utility of AUD pharmacotherapy in patients on immunosuppressive medications and those with renal impairment after liver transplantation. We also propose a comprehensive and objective definition of relapse utilizing contemporary biomarkers to guide future clinical trials. Future research using the proposed approach and definition is warranted with the goal of optimizing AUD treatment in patients with cirrhosis, the transplant selection process and post-transplantation care of patients with AUD.In this Review, Arab and colleagues discuss management of alcohol use disorder in patients with alcohol-associated liver disease, particularly in the setting of liver transplantation. An integrative, multidisciplinary approach is proposed.

The burden of liver disease is substantial and increasing; the impact of comorbid chronic diseases on the clinical course of patients with compensated and decompensated cirrhosis is not well-defined. The aim of this study was to examine the individual and additive impact of comorbid chronic diseases on mortality in patients with cirrhosis. In this population-based study, we used Cox proportional hazards modeling with time-dependent covariates to assess the impact of comorbid chronic diseases (diabetes mellitus, chronic kidney disease, and cardiovascular disease [CVD]) on mortality in patients with cirrhosis in a large, diverse Metroplex. There were 35,361 patients with cirrhosis (mean age 59.5 years, 41.8% females, 29.7% non-White, and 17.5% Hispanic ethnicity). Overall, the presence of chronic comorbidities was 1 disease (28.9%), 2 diseases (17.5%), and 3 diseases (12.6%) with a majority having CVD (45%). Adjusted risk of mortality progressively increased with an increase in chronic diseases from 1 (hazard ratio [HR] 2.5, 95% confidence interval [CI] 2.23-2.8) to 2 (HR 3.27.95% CI 2.9-3.69) to 3 (HR 4.52, 95% CI 3.99-5.12) diseases. Survival of patients with compensated cirrhosis and 3 chronic diseases was similar to subsets of decompensated cirrhosis (67.7% as compared with decompensated cirrhosis with 1-3 conditions, 61.9%-63.9%). In patients with cirrhosis, a focus on comorbid chronic disease(s) as potential management targets may help avoid premature mortality, regardless of etiology. Multidisciplinary care early in the clinical course of cirrhosis is needed in addition to the current focus on management of complications of portal hypertension.

Metabolic dysfunction associated steatotic liver disease (MASLD) has been associated with increased risks of all-cause and cardiovascular disease (CVD) mortality. Identification of modifiable risk factors that may contribute to higher risks of mortality could facilitate targeted and intensive intervention strategies in this population. This study aims to examine whether the magnesium depletion score (MDS) is associated with all-cause and CVD mortality among individuals with MASLD or metabolic and alcohol associated liver disease (MetALD). Methods: A total of 3802 participants with MASLD or MetALD were followed up over a median of 26 years in the National Health and Nutrition Examination Survey (NHANES) III cohort. The MDS was calculated by aggregating four factors influencing the reabsorption capability of the kidneys. The associations between MDS and all-cause, CVD, and cancer mortality were quantified using Cox proportional hazard regression models. Results: In the combined MASLD + MetALD cohort, a higher MDS (>2) was associated with increased all-cause mortality (HR, 2.52; 95%CI, 1.77–3.61; p-trend < 0.0001) and CVD mortality (HR, 3.01; 1.87–4.86; p-trend < 0.0001) compared to MDS = 0; this association became stronger among participants who did not meet the estimated average requirement level of Mg intake (2.72; 1.69–4.37; p-trend = 0.0014) and those with a Fibrosis-4 index (FIB-4) < 1.3 (2.95; 1.69–5.15; p-trend = 0.0006). Conclusions: In individuals with MASLD or MetALD, higher MDS, indicative of worse global Mg status, was associated with an increased risk of all-cause and CVD mortality. Correcting global Mg deficiency in high-risk MASLD/MetALD patients may have long-term health benefits.

Background and Objectives: Current guidelines recommend contrast-enhanced CT/MRI as confirmatory imaging tests for diagnosing hepatocellular carcinoma (HCC). However, these modalities are not always able to differentiate HCC from benign/dysplastic nodules that are commonly observed in cirrhotic livers. Consequently, many lesions require either pathological confirmation via invasive biopsy or surveillance imaging after 3–6 months, which results in delayed diagnosis and treatment. We aimed to develop noninvasive imaging biomarkers of liver cell size and cellularity, using magnetic resonance imaging (MRI), and to assess their utility in identifying HCC. Methods: MR cytometry combines measurements of water diffusion rates over different times corresponding to probing cellular microstructure at different spatial scales. Maps of microstructural properties, such as cell size and cellularity, are derived by fitting voxel values in multiple diffusion-weighted images to a three-compartment (blood, intra-, and extracellular water) model of the MRI signal. This method was validated in two phases: (1) histology-driven simulations, utilizing segmented histological images of different liver pathologies, and (2) ex vivo MR cytometry performed on fixed human liver specimens. Results: Both simulations and ex vivo MR cytometry of fixed human liver specimens demonstrated that HCC exhibits significantly smaller cell sizes and higher cellularities compared to normal liver and cirrhotic regenerative nodules. Conclusion: This study highlights the potential of MR cytometry to differentiate HCC from non-HCC lesions by quantifying cell size and cellularity in liver tissues. Our findings provide a strong foundation for further research into the role of MR cytometry in the noninvasive early diagnosis of HCC.

INTRODUCTION:Drug-induced liver injury (DILI) is a leading cause of acute liver injury in the US, most commonly caused by antibiotics and NSAIDS. The clinical history and biochemical pattern are often the most important clues to the diagnosis and a classic pattern can save the patient an invasive procedure such as liver biopsy. It becomes diagnostically challenging when the biochemical presentation is inconsistent with the drug reported, such as in this case.CASE DESCRIPTION/METHODS:A 34-year old Caucasian man presented to the hospital with progressive jaundice, vomiting and malaise. Medical history is remarkable for Ankylosing Spondylitis (AS) for which he is on Secukinumab, and for acute sinusitis diagnosed 23 days prior in clinic for which he completed a 10-day course Amoxicillin-Clavulanate (AC). Liver tests from 15 months prior were normal. Liver tests on presentation were remarkable for total bilirubin of 4.5 mg/dL, AST of 163 U/L, ALT of 449 U/L, and ALP of 132 U/L and peaked at total bilirubin of 12.5mg/dL, AST of 702 U/L, ALT of 1,292 U/L and ALP of 184 U/L. Viral hepatitis panel was notable for Hepatitis A and B immunity and Hepatitis C IgG positive but with undetectable viral load. Autoimmune hepatitis markers were also normal. In view of the progressive uptrend in transaminases despite medication discontinuation, hepatocellular biochemical pattern, and history of autoimmune disease (i.e., AS), autoimmune hepatitis was suspected and a liver biopsy was done. Liver biopsy was notable for mild mixed portal inflammation and bile duct distortion. The overall impression was DILI. He resumed Secukinumab but not AC. Upon follow up one month later, his liver tests completely normalized.DISCUSSION:AC-DILI presents most frequently among elderly men with a cholestatic biochemical pattern and self-limited course. AC-DILI of hepatocellular pattern is rare in adult patients, although more common among pediatric patients. Our report, interestingly, describes a distinct hepatocellular biochemical pattern of AC-DILI in an adult male patient with an underlying autoimmune disease. HLA B-27 allele (class I) is a strong genetic risk factor for the development of AS. Studies have shown that predisposition to AC-DILI is influenced by certain HLA haplotypes perhaps suggesting an involvement of the adaptive immune system. However, further studies are needed to determine whether this association might increase risk for organ injury as in DILI or if it alters the pattern of presentation and expected clinical course.

The current diagnostic gold standard for metabolic dysfunction-associated steatohepatitis (MASH) requires invasive biopsy to assess steatosis, inflammation, and ballooning. While MRI-based proton density fat fraction (PDFF) and MR elastography address steatosis and fibrosis, non-invasive methods for evaluating hepatic inflammation remain lacking. This study developed a diffusion MRI (dMRI)-based MR cytometry technique to map liver cellular properties, including MRI-derived cell size (excluding fat content) and cell density. Validation through histology-driven simulations and ex vivo MRI of fixed human liver specimens demonstrated that stromal regions exhibit smaller MRI-derived cell sizes and higher cell densities than both normal and fatty tissues. An in vivo feasibility study, conducted on healthy subjects ( n  = 5) and MASH patients ( n  = 5) using a clinical 3 T MRI system, further showcased the potential of MR cytometry to characterize pathological changes in liver microstructure.

Post‐transplant diabetes mellitus (PTDM) is a significant contributor to morbidity and mortality in liver transplant recipients (LTRs). With concurrent comorbidities and use of various immunosuppression medications, identifying a safe and personalized regimen for management of PTDM is needed. There are many comorbidities associated with the post‐transplant course including chronic kidney disease, cardiovascular disease, allograft steatosis, obesity, and de novo malignancy. Emerging data suggest that available diabetes medications may carry beneficial or, in some cases, harmful effects in the setting of these co‐existing conditions. Sodium‐glucose co‐transporter 2 inhibitors and glucagon‐like peptide 1 receptor agonists have shown the most promising beneficial results. Although there is a deficiency of LTR‐specific data, they appear to be generally safe. Effects of other medications are varied. Metformin may reduce the risk of malignancy. Pioglitazone may be harmful in patients combatting obesity or heart failure. Insulin may exacerbate obesity and increase the risk of developing malignancy. This review thoroughly discusses the roles of these extra‐glycemic effects and safety considerations in LTRs. Through weighing the risks and benefits, we conclude that alternatives to insulin should be strongly considered, when feasible, for personalized long‐term management based on risk factors and co‐morbidities.

Background Obesity is commonly observed in patients with cirrhosis, especially with the increasing prevalence of non-alcoholic steatohepatitis (NASH). Bariatric surgery has been avoided in these patients given concerns about increased perioperative risk; therefore, data are lacking regarding long-term outcomes. In this study, we aimed to evaluate the long-term outcomes of patients with cirrhosis who underwent bariatric surgery. Methods We reviewed the charts of adult patients with compensated cirrhosis who underwent bariatric surgery after they were prospectively enrolled between February 23, 2009 and November 9, 2011, and followed in a pilot study for evaluation of bariatric surgery outcomes. Only patients with more than 4 years of follow-up were included in the analysis. Data regarding their liver disease, metabolic status, and survival were collected. A descriptive analysis was performed. Results The cohort consisted of 10 patients, of whom 7 were females. The median post-surgical follow-up was 8.7 years (± 1.4 years). All patients had biopsy-proven NASH; two patients had concurrent, untreated hepatitis C infection. During the observation period, there was a mean weight loss of 24 kg (19.2% of total body weight pre surgery, P < 0.001) and only one patient regained weight to the baseline pre-surgical measurement. One patient who was not eligible for transplant developed hepatic encephalopathy 3 years after surgery and later died. The remainder of the patients did not have any hepatic decompensation, cardiovascular event, or mortality. Except for one patient with Gilbert syndrome, bilirubin was normal in all patients at last follow-up. Conclusions Bariatric surgery in patients with compensated cirrhosis can lead to sustained weight loss and stable hepatic function on long-term follow-up.