End-stage Cirrhosis Research Articles

Development and validation of a practical prognostic nomogram for evaluating inpatient mortality of cirrhotic patients with acute variceal hemorrhage

Introduction and ObjectivesCirrhotic patients with acute variceal hemorrhage (AVH) have high short-term mortality. Established prognostic scores are seldom applicable clinically, partially because they need external validation or contain subjective variables. We aimed to develop and validate a practical prognostic nomogram based on objective predictors to predict prognosis for cirrhotic patients with AVH. Patients and MethodsWe enrolled 308 AVH patients with cirrhosis from our center as the derivation cohort to develop a new nomogram using logistic regression and validated it in cohorts of patients from Medical Information Mart for Intensive Care (MIMIC) III (n = 247) and IV (n = 302). ResultsInternational normalized ratio (INR), albumin (ALB) and estimated glomerular filtration rate (eGFR) were identified as predictors for inpatient mortality and a nomogram was constructed based on them. The nomogram discriminated well in both derivation and MIMIC-III/-IV validation cohorts with the area under the receiver operating characteristic curves (AUROCs) of 0.846 and 0.859/0.833, respectively and showed a better agreement between expected and observed outcomes (Hosmer-Lemeshow tests, all comparisons, P > 0.05) than other scores in all cohorts. Our nomogram had the lowest Brier scores (0.082/0.114/0.119 in training/MIMIC-III/MIMIC-IV) and highest R2 (0.367/0.393/0.346 in training/MIMIC-III/MIMIC-IV) compared to the recalibrated model for end-stage liver disease (MELD), MELD-hepatic encephalopathy (MELD-HE) and cirrhosis acute gastrointestinal bleeding (CAGIB) scores in all cohorts. ConclusionsWe developed a practical prognostic nomogram using easily verified indicators available in initial patient evaluation, which may serve as a reliable tool to accurately predict inpatient mortality for cirrhotic patients with AVH.

Первичный билиарный холангит: новая дефиниция заболевания, актуальные аспекты диагностики и лечения. Обзор литературы

Primary biliary cholangitis (PBc) is a chronic autoimmune cholestatic liver disease characterized by T-lymphocyte-mediated damage to intrahepatic biliary epithelial cells and the presence of a specific serological marker, antimitochondrial antibodies, and which, if left untreated, leads to end-stage biliary cirrhosis. PBc remains a major public health problem. until recently, PBc was referred to as "primary biliary cirrhosis", but the disease is often diagnosed in the pre-cirrhotic phase, when there is no formed cirrhosis yet, but there is only a threat of its development. The change in the definition of the disease harmoniously fits into the framework of the concept of preventive medicine, since with timely diagnosis and adequate therapy, this phase of the disease can be extended for years and decades, but all these years the patient is “traumatized” by a prediagnosed liver cirrhosis. At the end of the previous decade, a large number of international clinical recommendations and guidelines on PBc were published. As part of the review of the current state of the PBc problem, publications from various international databases were used, with an emphasis on publications of the current decade, which note the importance of early diagnosis of the disease with an emphasis on biochemical markers of cholestasis (primarily alkaline phosphatase) and immunological markers (primarily turn antimitochondrial antibodies) and early initiation of treatment with the first-line drug – ursodeoxycholic acid. Keywords: primary biliary cholangitis, definition of the disease, epidemiology, diagnosis, alkaline phosphatase, antimitochondrial antibodies, clinic, treatment, ursodeoxycholic acid, obeticholic acid, monitoring, prognosis.

Hepatorenaal syndroom na embolisatie van een splenorenale shunt

Hepatorenal syndrome after embolisation of a splenorenal shunt This article discusses a case of hepatorenal syndrome after therapeutic embolisation of a splenorenal shunt in a patient with recurrent hepatic encephalopathy. The hepatorenal syndrome is a unique form of acute kidney failure in patients with end-stage liver cirrhosis and ascites. In this case, no known triggering factors were found, so it was evaluated if the embolisation of the portosystemic shunt can predispose to the emergence of a hepatorenal syndrome.

Does COVID-19 infection significantly affect liver transplantation? Results of liver transplantation in the COVID-19 era at a single, high-volume centre

BackgroundLiver transplantation is a proven management method for end-stage cirrhosis and is estimated to have increased life expectancy by 15 years. The COVID-19 pandemic posed a challenge to patients who...

C-C motif chemokine receptor 2 inhibition reduces liver fibrosis by restoring the immune cell landscape.

The accumulation of extracellular matrix (ECM) proteins in the liver leads to liver fibrosis and end-stage liver cirrhosis. C-C motif chemokine receptor 2 (CCR2) is an attractive target for treating liver fibrosis. However, limited investigations have been conducted to explore the mechanism by which CCR2 inhibition reduces ECM accumulation and liver fibrosis, which is the focus of this study. Liver injury and liver fibrosis were induced by carbon tetrachloride (CCl4) in wild-type mice and Ccr2 knockout (Ccr2-/-) mice. CCR2 was upregulated in murine and human fibrotic livers. Pharmacological CCR2 inhibition with cenicriviroc (CVC) reduced ECM accumulation and liver fibrosis in prevention and treatment administration. In single-cell RNA sequencing (scRNA-seq), CVC was demonstrated to alleviate liver fibrosis by restoring the macrophage and neutrophil landscape. CVC administration and CCR2 deletion can also inhibit the hepatic accumulation of inflammatory FSCN1+ macrophages and HERC6+ neutrophils. Pathway analysis indicated that the STAT1, NFκB, and ERK signaling pathways might be involved in the antifibrotic effects of CVC. Consistently, Ccr2 knockout decreased phosphorylated STAT1, NFκB, and ERK in the liver. In vitro, CVC could transcriptionally suppress crucial profibrotic genes (Xaf1, Slfn4, Slfn8, Ifi213, and Il1β) in macrophages by inactivating the STAT1/NFκB/ERK signaling pathways. In conclusion, this study depicts a novel mechanism by which CVC alleviates ECM accumulation in liver fibrosis by restoring the immune cell landscape. CVC can inhibit profibrotic gene transcription via inactivating the CCR2-STAT1/NFκB/ERK signaling pathways.

A Retrospective Analysis of Bone Marrow Examination Results from a Single Center Institution: In What Situations Is Bone Marrow Examination Helpful?

Objective: Bone marrow (BM) examinations are performed to evaluate hematological abnormalities. Focusing on patients with cytopenia, we aimed to determine the circumstances under which a BM examination can assist in the diagnosis of hematologic diseases.Methods: The medical records of 738 patients who underwent BM examination from March 2011 to March 2019 at Soonchunhyang University Seoul Hospital were reviewed. In total, 234 patients underwent a BM examination to identify the cause of cytopenia. Excluded from the analysis were BM examinations performed to diagnose specific diseases and evaluate disease status.Results: Results suggesting suboptimal outcome (n=6) or BM invasion of solid tumors (n=13) were excluded. Immune thrombocytopenic purpura patients (n=52) with normal BM examination results were also excluded. One hundred sixty-three patients who underwent BM examination to determine the cause of cytopenia were included in the analysis. A comparison of non-specific results (n=56) to those pointing to an underlying hematologic disease (n=107) showed that patients with severe neutropenia or severe thrombocytopenia were more likely to be diagnosed with a hematologic disease. Specifically, as the number of severe cytopenias increased, the likelihood of a hematologic disease diagnosis was significantly augmented. Patients with end-stage renal disease, autoimmune disease, or liver cirrhosis were more likely to receive non-specific results.Conclusion: In conclusion, seeking the underlying disease or drug should be a primary target for patients with cytopenia. In cases of severe cytopenia in more than one lineage, BM examination should be strongly considered to diagnose an underlying hematologic disease.

Liver fibrosis is associated with impaired bone mineralization and microstructure in obese individuals with non-alcoholic fatty liver disease.

Chronic liver diseases are associated with increased bone fracture risk, mostly in end-stage disease and cirrhosis; besides, data in non-alcoholic fatty liver disease (NAFLD) are limited. Aim of this study was to investigate bone mineralization and microstructure in obese individuals with NAFLD in relation to the estimated liver fibrosis. For this cross-sectional investigation, we analyzed data from 1872 obese individuals (44.6 ± 14.1years, M/F: 389/1483; BMI: 38.3 ± 5.3kg/m2) referring to the Endocrinology outpatient clinics of Sapienza University, Rome, Italy. Participants underwent clinical work-up, Dual-Energy X-ray Absorptiometry for assessing bone mineral density (BMD) and microarchitecture (trabecular bone score, TBS). Liver fibrosis was estimated by Fibrosis Score 4 (FIB-4). Serum parathyroid hormone (PTH), 25(OH) vitamin D, osteocalcin and IGF-1 levels were measured. Obese individuals with osteopenia/osteoporosis had greater FIB-4 than those with normal BMD (p < 0.001). FIB-4 progressively increased in presence of degraded bone microarchitecture (p < 0.001) and negatively correlated with the serum osteocalcin (p < 0.001) and IGF-1 (p < 0.001), which were both reduced in presence of osteopenia/osteoporosis. FIB-4 predicted IGF-1 reduction in multivariable regression models adjusted for confounders (β: -0.18, p < 0.001). Higher FIB-4 predicted bone fragility with OR 3.8 (95%C.I:1.5-9.3); this association persisted significant after adjustment for sex, age, BMI, diabetes, smoking status and PTH at the multivariable logistic regression analysis (OR 1.91 (95%C.I:1.15-3.17), p < 0.01), with AUROC = 0.842 (95%C.I:0.795-0.890; p < 0.001). Our data indicate the presence of a tight relation between NAFLD-related liver fibrosis, lower bone mineral density and degraded microarchitecture in obese individuals, suggesting potential common pathways underlying liver and bone involvement in obesity and insulin resistance-associated disorders.

Emerging Role of NLRP3 Inflammasome and Pyroptosis in Liver Transplantation.

The nucleotide-binding domain leucine-rich repeat-receptor, pyrin domain-containing-3 (NLRP3) inflammasome contributes to the inflammatory response by activating caspase-1, which in turn participates in the maturation of interleukin (IL)-1β and IL-18, which are mainly secreted via pyroptosis. Pyroptosis is a lytic type of cell death that is controlled by caspase-1 processing gasdermin D. The amino-terminal fragment of gasdermin D inserts into the plasma membrane, creating stable pores and enabling the release of several proinflammatory factors. The activation of NLRP3 inflammasome and pyroptosis has been involved in the progression of liver fibrosis and its end-stage cirrhosis, which is among the main etiologies for liver transplantation (LT). Moreover, the NLRP3 inflammasome is involved in ischemia-reperfusion injury and early inflammation and rejection after LT. In this review, we summarize the recent literature addressing the role of the NLRP3 inflammasome and pyroptosis in all stages involved in LT and argue the potential targeting of this pathway as a future therapeutic strategy to improve LT outcomes. Likewise, we also discuss the impact of graft quality influenced by donation after circulatory death and the expected role of machine perfusion technology to modify the injury response related to inflammasome activation.

Integrated Analysis of mRNA and lncRNA Expression Profiles Reveals Regulatory Networks Associated with Decompensated Cirrhosis.

The stage of decompensation is termed end-stage liver cirrhosis. Patients with decompensated cirrhosis (DCC) often have a variety of comorbidities that contribute to exacerbation of the disease and its high mortality rate. By comparing differential gene expression, transcriptomic analysis is useful for exploring relevant functional changes during disease progression. The purpose of this study was to identify differentially expressed long noncoding RNAs (lncRNAs) and mRNAs in patients with decompensated cirrhosis and to further explore the functions as well as interactions between lncRNAs and mRNAs. Four patients with decompensated cirrhosis and four controls with liver cirrhosis were recruited in this study. RNA was isolated from peripheral blood mononuclear cells, and RNA-seq was used for transcriptome analysis. The functions of differentially expressed mRNAs were revealed by Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, and a regulatory network was also constructed. A total of 1046 differentially expressed mRNAs and 1175 lncRNAs were identified between the decompensated cirrhosis patients and cirrhosis controls. Functional enrichment analyses indicated enrichment of genes involved in pathways related to inflammation and cellular metabolic activities. In addition, the findings suggested that the phagosome/endosome/autophagy-lysosome pathway might play an important role in cirrhotic decompensation. In summary, this study identified differentially expressed mRNAs (DE-mRNAs) and DE-lncRNAs and predicted the biological processes and signaling pathways involved in cirrhotic decompensation, which might provide new ideas for further revealing the molecular mechanism of DCC pathogenesis.

Heme oxygenase-1 mitigates liver injury and fibrosis via modulation of LNX1/Notch1 pathway in myeloid cells

SummaryActivation of resident macrophages (Mϕ) and hepatic stellate cells is a key event in chronic liver injury. Mice with heme oxygenase-1 (HO-1; Hmox1)-deficient Mϕ (LysM-Cre:Hmox1flfl) exhibit increased inflammation, periportal ductular reaction, and liver fibrosis following bile duct ligation (BDL)-induced liver injury and increased pericellular fibrosis in NASH model. RiboTag-based RNA-sequencing profiling of hepatic HO-1-deficient Mϕ revealed dysregulation of multiple genes involved in lipid and amino acid metabolism, regulation of oxidative stress, and extracellular matrix turnover. Among these genes, ligand of numb-protein X1 (LNX1) expression is strongly suppressed in HO-1-deficient Mϕ. Importantly, HO-1 and LNX1 were expressed by hepatic Mϕ in human biliary and nonbiliary end-stage cirrhosis. We found that Notch1 expression, a downstream target of LNX1, was increased in LysM-Cre:Hmox1flfl mice. In HO-1-deficient Mϕ treated with heme, transient overexpression of LNX1 drives M2-like Mϕ polarization. In summary, we identified LNX1/Notch1 pathway as a downstream target of HO-1 in liver fibrosis.

Individualized total laparoscopic surgery based on 3D remodeling for portal hypertension: A single surgical team experience.

Background and aimsPortal hypertension (PHT) is common in end-stage cirrhosis, and variceal bleeding is the main complication associated with mortality. Surgery is usually performed in patients with PHT with a high risk of variceal bleeding in China. This study aimed to introduce an individualized and precise total laparoscopic surgical procedure based on 3D remodeling for PHT.MethodsFrom March 2013 to December 2018, 146 patients with cirrhotic PHT underwent a laparoscopic surgical procedure in our department. An individualized 3D remodeling evaluation was carried out for surgical planning.ResultsThe operation time was 319.96 ± 91.53 min. Eight of 146 patients were converted to open surgery. Acute portal vein system thrombosis occurred in 10 patients (6.85%). During the first year, 11 patients (8.15%) experienced rebleeding and two (1.48%) died. 18 patients (13.33%) experienced rebleeding and three died, giving a 3-year mortality rate of 3.66%. Compared with preoperatively, the portal vein showed significant postoperative decreases in diameter, flow velocity, and flow amount, while the hepatic artery showed significant postoperative increases in diameter, flow velocity, and flow amount. A 3D liver volume evaluation found that 19 of 21 patients had a significantly increased liver volume postoperatively, and a significantly decreased MELD score.ConclusionThis retrospective study introduced a safe, feasible, and effective individualized surgical procedure. Our results show that this surgical treatment may not only act as an effective symptomatic treatment for PHT to prevent esophageal and gastric hemorrhage, but also as an etiological treatment to increase liver function and long-term survival.

A Review on Biomarkers for the Evaluation of Autoimmune Cholestatic Liver Diseases and Their Overlap Syndromes.

Autoimmune cholestatic liver disease includes both Primary Biliary Cholangitis (PBC) and Primary Sclerosing Cholangitis (PSC). Both conditions result in impairment of hepatic bile flow ultimately leading to chronic liver injury, liver fibrosis and eventually end stage cirrhosis. Early and accurate diagnosis are important for the risk stratification, follow up and management of these patients. The underlying pathogenesis of these conditions have not been completely resolved and poses a barrier for the development of new diagnostic and prognostics tools. Current research work suggests that the pathogenesis of autoimmune cholestatic liver disease results from environmental, genetic, and a large component of underlying immune dysfunction. While the current available serum biomarkers and imaging modalities showcases progression in precision medicine for the management of autoimmune cholestatic liver disease, development of new biomarkers are still an area of need in this field. In this review, we will discuss the current and emerging biomarkers in patients with PBC, PSC, and a special population that exhibit overlap syndrome with autoimmune hepatitis (AIH). The use of these biomarkers for diagnosis and prognosis of these patients will be reviewed through the lens of the current understanding of the complex immune pathophysiology of these conditions.

Гепаторенальний синдром у дитини з муковісцидозом: аналіз клінічного випадку

Hepato-renal syndrome (HRS) is a rare complication that may accompany end-stage cystic fibrosis-associated cirrhosis in patients with cystic fibrosis. There is currently no unified protocol for the diagnosis and treatment of HRS in cystic fibrosis, particularly in pediatric patients. The main approaches to diagnosing the condition are to detect signs of acute renal failure in a patient with severe liver damage in the absence of shock and in the absence of signs of organic kidney damage or the use of nephrotoxic drugs. Treatment is based on the appointment of vasoconstrictors in combination with albumin infusion and the exclusion of factors that promote the development of HRS, but the method of final therapy remains liver transplantation. The article presents an analysis of the clinical case of HRS and its treatment in a child with cystic fibrosis. Immediate detection of liver cirrhosis in patients with cystic fibrosis, exclusion of the risk factors (massive and protracted surgical interventions, significant volume of extracted ascitic rudin, limiting the use of nephrotoxic drugs and high-dose loop diuretics) is a way to prevent the development of severe liver cirrhosis complications. Immediate recognition and proper management of HRS is a way to protect life before liver transplantation, as well as to preserve the quality of life of patients with cystic fibrosis. The research was carried out in accordance with the principles of the Helsinki Declaration. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors. Key words: cystic fibrosis, hepatorenal syndrome, liver cirrhosis, ascites, terlipressin.

Albumin therapy for hepatic encephalopathy: current evidence and controversies.

Hepatic encephalopathy (HE) is a common complication that occurs in 16-21% of end-stage cirrhosis patients. Emerging evidence suggests that systemic inflammation and oxidative stress may play a role in the development of HE. Recent understanding on the anti-inflammatory properties of human albumin has led to growing interest of using human albumin for the treatment and prevention of HE among decompensated patients. In this review, we aim to discuss the current evidence and controversies of using human albumin for the treatment and prevention of HE in advanced cirrhosis patients.

Nutritional Deficiencies and Clinical Practices in Decompensated Cirrhotics With Hepatic Encephalopathy.

BackgroundHepatic encephalopathy (HE), a major complication of end-stage cirrhosis, is often associated with nutritional deficiencies. We aimed to assess the frequency in which vitamins and zinc were tested for and deficient in our cirrhotic population with HE.MethodsWe performed a retrospective chart review of 143 patients with decompensated cirrhosis that were seen in a hepatology clinic from January 2020 to May 2021. Patient demographics and decompensations were recorded. Vitamins and minerals that were evaluated included zinc, vitamin B12, folate, vitamin D, and thiamine. Continuous variables were reported as mean ± standard deviation and categorical variables were calculated as frequency percentages.ResultsOut of 143 patients, 73 were found to have HE. Out of 73, 33 were male, and the average MELD was 15.5 ± 6.3. 44% of patients had NASH cirrhosis, and 30% had alcoholic cirrhosis. Of the minority of patients that had their nutrient levels checked, 17/23 (74%) were deficient in zinc (<60 mcg/dL). 75% of patients were deficient in thiamine. 2/34 (6%) were deficient in folate (<5.9 ng/mL), 2/10 (20%) in vitamin D (<20 ng/mL), and 2/47 (4%) in B12 (<300 pg/mL).ConclusionNutritional deficiencies are common in cirrhotics with HE. Further studies are needed to determine if routine testing and treatment for vitamin and Zinc deficiencies would have a positive impact on the clinical trajectory of HE.

Methadone-related death in detention

Oral methadone may be prescribed to detainees with the aim of minimising the risk of fatal opioid poisoning on release. To study the circumstances under which methadone-related deaths can occur in detention, we audited reports of 17 [14 male, 3 female; median (range) age 34 (22–52) years] such deaths, July 2010–December 2011. The median (range) methadone dose was 40 (10–110) mg/d (N = 16). The median (range) post-mortem blood methadone concentration was 0.42 (0.16–1.40) mg/L. Those who died within 7 days of the commencement of methadone treatment were significantly younger (Mann-Whitney U 102.5, p < 0.05), were prescribed a significantly lower dose (U = 80.0, p < 0.05) and had significantly lower blood methadone concentrations at death (U = 106.5, p < 0.02) than in those given methadone long-term. In 8 reports the prisoner had been recorded as either ‘sleepy’ (N = 7), or ‘unwell’ in the hours before death. In 13 deaths, the prisoner was either found dead first thing in the morning, or in one instance could not be roused (‘snoring heavily’). Pneumonia, tracheobronchitis, end-stage cirrhosis, and ischaemic heart disease/coronary artery atherosclerosis were cited as associated factors in four patients, all of whom were on long term stable methadone treatment. Attention to warning signs of likely methadone toxicity (daytime or excessive drowsiness, snoring, nausea/vomiting) and associated risk factors (use of drugs such as benzodiazepines and gabapentinoids, the presence of respiratory infection, liver or renal disease) could help minimise the risk of unexpected death in patients given methadone.

Assessment of Three-Phasic CT Scan Findings of Cirrhosis Due to Primary Sclerosing Cholangitis Versus Cryptogenic Cirrhosis.

Background: The CT findings of cirrhosis caused by primary sclerosing cholangitis (PSC) differ from cryptogenic cirrhosis. PSC could become complicated with biliary cirrhosis and cholangiocarcinoma. This study aimed at augmenting the information on the role of the three-phasic-abdominopelvic CT scan in PSC.Material and methods: A total of 185 CT scans were retrospectively reviewed, including 100 patients with cryptogenic cirrhosis and 85 patients with PSC-cirrhosis. Different morphologic criteria were compared, including segmental atrophy/hypertrophy, hepatic contour, portal-hypertension, perihilar lymphadenopathy, biliary tree dilatation, gallbladder appearance. Inflammatory-bowel-disease (IBD) and cholangiocarcinoma frequency, presence of perihilar lymph nodes (LNs), and their size during end-stage PSC cirrhosis are investigated.Results: Six findings occur more frequently with PSC than those diagnosed with cryptogenic cirrhosis. Modified caudate/right lobe (m-CRL) ratio >0.73, moderate and severe lobulated liver contour, lateral left lobe atrophy, over distended gallbladder (GB), biliary tree dilatation and wall thickening, and LN sizes were higher in PSC patients as compared to cryptogenic cirrhosis (P < 0.005). Ascites and portosystemic collateral formations were significant in cryptogenic cirrhosis compared to PSC patients (P < 0.005). Cholangiocarcinoma frequency in PSC patients was 14.7%, and the frequency of inflammatory bowel disease (IBD) was 57.6%. Further, 22.4% of the patients were diagnosed with IBD and PSC simultaneously. The LN number and size in PSC patients were not different between those with or without cholangiocarcinoma.Conclusion: Using three-phasic CT scans and PSC characteristics could be considered as an additional suggestion besides pathology measures. Diagnosis of PSC based on histological findings could be a last resort due to its invasive essence and specific characteristics of PSC in imaging.

Long Term Safety and Outcomes Utilizing the CardioMEMS Device in Patients with Pulmonary Arterial Hypertension

<h3>Purpose</h3> Baseline and periodic hemodynamic monitoring of pulmonary artery pressures using right heart catheterization (RHC) is recommended for initiating and titrating pulmonary arterial hypertension (PAH) therapies as well as for prognostication. The CardioMEMS HF System is an ambulatory implantable hemodynamic monitor, previously only used in patients with left heart failure (HF). In this study, we describe the long-term safety and outcomes using the CardioMEMS device in PAH patients implanted as a part of an investigational pilot study. <h3>Methods</h3> 23 PAH patients between the ages of 31-80 years, were implanted with CardioMEMS device as a part of an investigational pilot study (VITA contract HHSN268201400008C) between 08/2014 - 09/2018. 3 patients were lost to follow-up. Complete follow up data was available for 20 patients who were included in this analysis. <h3>Results</h3> 85% of the PAH patients were female, with a median post-implant follow-up period of 58.5 months. The number of right heart catheterization (RHC) prior to the device implant was 4.37 per patient year, while only 1.99 RHC per patient year were done post implant. In long term follow up there were no significant device related adverse events and all devices remain functional. 8 patients did require RHC for recalibration of the device. 12 patients are still undergoing active monitoring. Of the remaining patients, 1 was enrolled in hospice, 4 patients died from progression of PAH, 1 patient died from malignancy; 1 from end-stage cirrhosis. There was a total of 13 HF hospitalizations between these 20 patients over 3 to 7 year follow-up based on the time of implant. <h3>Conclusion</h3> The CardioMEMS device has previously been reported to reduce hospitalizations in patients with left sided heart failure. Based on our study, deployment of the device was safe in PAH patients with no long-term device related complications. It reduced the number of follow-up invasive RHC by more than 50%. Larger prospective studies are warranted before widespread use of the device for monitoring PA pressures in PAH patients.

Cholesterol Induces Oxidative Stress, Mitochondrial Damage and Death in Hepatic Stellate Cells to Mitigate Liver Fibrosis in Mice Model of NASH.

Liver fibrosis and its end-stage disease cirrhosis are major world health problems arising from chronic injury of the liver. In recent years, the hypothesis that hepatic stellate cells’ (HSCs’) activation and fibrosis can be mitigated by HSC apoptosis and cell death has become of interest. In the current study, we evaluated the effect of cholesterol and bile acids on HSC apoptosis and liver fibrosis. Male C57BL/6J mice (wild type), aged four to five weeks, were fed an AIN-93G based diet (normal diet, ND), ND diet + 1% (w/w) cholesterol (CHOL group), ND diet + 0.5% (w/w) cholic acid (CA group) or ND diet + 1% (w/w) cholesterol + 0.5% (w/w) cholic acid (CHOL + CA group). Female Mdr2(-/-) mice were also treated with ND with and without 1% cholesterol. The effect of cholesterol on liver fibrosis and HSC clearance was evaluated. In addition, we studied the mechanism of cholesterol-induced apoptosis in HSC-T6 and AML-12 hepatocyte cell lines. In animals treated with cholic acids, increased lipid peroxidation and fibrosis were observed after six weeks of treatment. However, addition of cholesterol to the diet of C57BL/6J mice led to HSC-specific apoptosis and resolution of liver fibrosis, verified by double-staining with active caspase and α smooth muscle actin antibodies. In Mdr2 (-/-) mice, a diet supplemented with cholesterol corrected fibrosis and induced active hepatic stellate cells’ clearance. HSC-T6 were found to be much more sensitive to cholesterol-induced oxidative stress, mitochondrial damage and apoptosis compared to hepatocytes. These results indicate that cholesterol may be a trigger of HSC lipid peroxidation and death in the liver in a model of non-alcoholic steatohepatitis. A high cholesterol-to-bile acid ratio may determine the trajectory of the liver disease toward mitigation of fibrosis.

NASH: regulatory considerations for clinical drug development and U.S. FDA approval.

Nonalcoholic fatty liver disease is a growing public health crisis, with phenotypes from nonalcoholic fatty liver to nonalcoholic steatohepatitis, currently known as NASH, which can progress to liver fibrosis and end stage cirrhosis. NASH is associated with an increased risk of cardiovascular disease and Type 2 diabetes mellitus. There are still no U.S. FDA approved drugs or biological treatments for NASH or related liver diseases. Despite official agency guidance, the regulatory pathway to ultimate product approval is unclear, due to both the extra-hepatic factors that contribute to NASH, as well as the organizational structure of FDA, with its traditional separation of therapeutic indications within discrete review divisions. There is hope that continued evolution of the regulatory process will lead to the ability for clinical trial endpoints supporting NASH treatment approval to include both liver-based and traditional metabolic measures, independent of specific FDA division review.