End Stage Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease that affects approximately one-quarter of the global adult population, posing a significant threat to human health with wide-ranging social and economic implications. The main characteristic of NAFLD is considered that the excessive fat is accumulated and deposited in hepatocytes without excess alcohol intake or some other pathological causes. NAFLD is a progressive disease, ranging from steatosis to non-alcoholic steatohepatitis (NASH), cirrhosis, hepatocellular carcinoma, liver transplantation, and death. Therefore, NAFLD will probably emerge as the leading cause of end-stage liver disease in the coming decades. Unlike other highly prevalent diseases, NAFLD has received little attention from the global public health community. Liver biopsy is currently considered the gold standard for the diagnosis and staging of NAFLD because of the absence of noninvasive and specific biomarkers. Due to the complex pathophysiological mechanisms of NAFLD and the heterogeneity of the disease phenotype, no specific pharmacological therapies have been approved for NAFLD at present, although several drugs are in advanced stages of development. This review summarizes the current evidence on the pathogenesis, diagnosis and treatment of NAFLD.

Liver disease is prevalent worldwide. When it reaches the end stage, mortality rises to 50% or more. Although liver transplantation has emerged as the most efficient treatment for end-stage liver disease, its application has been limited by the scarcity of donor livers. The lack of acceptable donor organs implies that patients are at high risk while waiting for suitable livers. In this scenario, cell therapy has emerged as a promising treatment approach. Most of the time, transplanted cells can replace host hepatocytes and remodel the hepatic microenvironment. For instance, hepatocytes derived from donor livers or stem cells colonize and proliferate in the liver, can replace host hepatocytes, and restore liver function. Other cellular therapy candidates, such as macrophages and mesenchymal stem cells, can remodel the hepatic microenvironment, thereby repairing the damaged liver. In recent years, cell therapy has transitioned from animal research to early human studies. In this review, we will discuss cell therapy in end-stage liver disease treatment, especially focusing on various cell types utilized for cell transplantation, and elucidate the processes involved. Furthermore, we will also summarize the practical obstacles of cell therapy and offer potential solutions.

ImportanceA high proportion of underserved patients with cirrhosis receive care at safety-net hospitals (SNHs). While liver transplant (LT) can be a life-saving treatment for cirrhosis, data on referral patterns from SNHs to LT centers are lacking.ObjectiveTo identify factors associated with LT referral within the SNH context.Design, setting, and participantsThis retrospective cohort study included 521 adult patients with cirrhosis and model for end-stage liver disease-sodium (MELD-Na) scores of 15 or greater. Participants received outpatient hepatology care at 3 SNHs between January 1, 2016, and December 31, 2017, with end of follow-up on May 1, 2022.ExposuresPatient demographic characteristics, socioeconomic status, and liver disease factors.Main outcomes and measuresPrimary outcome was referral for LT. Descriptive statistics were used to describe patient characteristics. Multivariable logistic regression was performed to evaluate factors associated with LT referral. Multiple chained imputation was used to address missing values.ResultsOf 521 patients, 365 (70.1%) were men, the median age was 60 (IQR, 52-66) years, most (311 [59.7%]) were Hispanic or Latinx, 338 (64.9%) had Medicaid insurance, and 427 (82.0%) had a history of alcohol use (127 [24.4%] current vs 300 [57.6%] prior). The most common liver disease etiology was alcohol associated liver disease (280 [53.7%]), followed by hepatitis C virus infection (141 [27.1%]). Median MELD-Na score was 19 (IQR, 16-22). One hundred forty-five patients (27.8%) were referred for LT. Of these, 51 (35.2%) were wait-listed, and 28 (19.3%) underwent LT. In a multivariable model, male sex (adjusted odds ratio [AOR], 0.50 [95% CI, 0.31-0.81]), Black race vs Hispanic or Latinx ethnicity (AOR, 0.19 [95% CI, 0.04-0.89]), uninsured status (AOR, 0.40 [95% CI, 0.18-0.89]), and hospital site (AOR, 0.40 [95% CI, 0.18-0.87]) were associated with lower odds of being referred. Reasons for not being referred (n = 376) included active alcohol use and/or limited sobriety (123 [32.7%]), insurance issues (80 [21.3%]), lack of social support (15 [4.0%]), undocumented status (7 [1.9%]), and unstable housing (6 [1.6%]).ConclusionsIn this cohort study of SNHs, less than one-third of patients with cirrhosis and MELD-Na scores of 15 or greater were referred for LT. The identified sociodemographic factors negatively associated with LT referral highlight potential intervention targets and opportunities to standardize LT referral practices to increase access to life-saving transplant among underserved patients.

ObjectivesEnd-stage chronic liver disease in children is associated with sarcopenia and aberrant adipose tissue mass. We investigated correlations between liver pathology-associated gene pathways (fibrosis, inflammation and steatosis) and metabolic genes in muscle and adipose tissue.MethodsLiver, rectus abdominis muscle and subcutaneous adipose tissue were collected during liver transplant for microarray gene expression analysis. Patients underwent pre-transplant indirect calorimetry, anthropometry and laboratory assessments. Weighted gene co-expression network analysis identified highly correlated gene modules within each tissue and explored inter-tissue correlations.ResultsNine patients were studied, three male:six female, age 7 months to 17 years. Liver gene clusters associated with fibrosis and ribosome function/protein secretion negatively correlated with muscle mitochondrial function genes and positively correlated with adipose tissue mitochondrial function genes. Notable correlations included a negative correlation between muscle growth hormone receptor (GHR) and liver ARID5B, MFGE8 and YWHAZ, and a positive correlation between adipose AKT1, ADG5, and SRM and liver RRAGA, YES1, EIF3M and COX3A. Liver inflammation-associated genes (vimentin, TIMP2, CXCL6 and endothelin-1) negatively correlated with adipose genes improving insulin sensitivity (THRSP) and fibrosis-related genes (KRT36, DMTN). Liver steatosis genes (ADRA2B) negatively correlated with adipose genes involved in adipogenesis (FGF10) and thyroid hormone metabolism (NHLH1).ConclusionsGenes related to liver fibrosis and protein secretion negatively correlated with muscle and adipose tissue metabolism/proliferation genes. Liver inflammation and steatosis gene clusters were associated with muscle and adipose metabolism genes. This pilot study highlights important inter-tissue gene correlations warranting further investigation in paediatric end-stage chronic liver disease.