Decompensated Cirrhosis Research Articles

Diagnostic role of CD64 expression on neutrophils as biomarker for blood stream infection in liver cirrhosis: some preliminary findings.

The expression of CD64 on neutrophils (nCD64), measured using flow cytometry, has been proposed as a biomarker for bloodstream infections (BSI). However, data regarding its use in the setting of liver cirrhosis are lacking. We compared nCD64 levels in 15 cirrhotic patients with BSI to those in 19 controls, including outpatients with stable decompensated cirrhosis without infection. Additionally, we compared nCD64 with C-reactive protein (CRP) and procalcitonin (PCT) in infected hospitalized cirrhotic patients. Cirrhotic patients with infection had higher levels of nCD64 compared to controls (6.0 [5.4-7.1] vs. 2.0 [1.5-2.2]; p<0.001). Among infected patients, a correlation between nCD64 (AUC=0.934 [0.875-0.982 95% CI]), CRP (AUC=0.972 [0.942-0.993 95% CI]), and PCT (AUC=0.859 [0.739-0.953 95% CI]) was observed. However, in our sample of cirrhotic individuals, nCD64 values were not significantly different between patients with worse prognosis and those with positive outcomes (p=0.448), and its expression was not influenced by Gram stain. In our cohort, nCD64 appears to be a promising new biomarker for BSI. Additional prospective studies are needed to confirm its role and limitations in conjunction with other biomarkers and rapid microbiology in the diagnostic multidisciplinary pathway for septic cirrhotic patients.

Liver-secreted FGF21 induces sarcopenia by inhibiting satellite cell myogenesis via klotho beta in decompensated cirrhosis

Background & aimsSarcopenia, a prevalent condition, significantly impacts the prognosis of patients with decompensated cirrhosis (DC). Serum fibroblast growth factor 21 (FGF21) levels are significantly higher in DC patients with sarcopenia. Satellite cells (SCs) play a role in aging- and cancer-induced sarcopenia. Here, we investigated the roles of FGF21 and SCs in DC-related sarcopenia as well as the underlying mechanisms. MethodsWe developed two DC mouse models and performed in vivo and in vitro experiments. Klotho beta (KLB) knockout mice in SCs were constructed to investigate the role of KLB downstream of FGF21. In addition, biological samples were collected from patients with DC and control patients to validate the results. ResultsMuscle wasting and impaired SC myogenesis were observed in the DC mouse model and patients with DC. Elevated circulating levels of liver-derived FGF21 were observed, which were significantly negatively correlated with skeletal muscle mass/skeletal muscle index. Liver-secreted FGF21 induces SC dysfunction, contributing to sarcopenia. Mechanistically, FGF21 in the DC state exhibits enhanced interactions with KLB on SC surfaces, leading to downstream phosphatase and tensin homolog upregulation. This inhibits the protein kinase B (PI3K/Akt) pathway, hampering SC proliferation and differentiation, and blocking new myotube formation to repair atrophy. Neutralizing circulating FGF21 using neutralizing antibodies, knockdown of hepatic FGF21 by adeno-associated virus, or knockout of KLB in SCs effectively improved or reversed DC-related sarcopenia. ConclusionsHepatocyte-derived FGF21 mediates liver-muscle crosstalk, which impairs muscle regeneration via the inhibition of the PI3K/Akt pathway, thereby demonstrating a novel therapeutic strategy for DC-related sarcopenia.

Altered blood microbiome in patients with HCV-related Child-Pugh class B cirrhosis

BackgroundAltered bacterial translocation is associated with changes in hepatic function and the progression from compensated to decompensated cirrhosis. Child-Turcotte-Pugh (CTP) score is an essential indicator of liver severity. Thus, we aimed to study differences in the blood microbiome together with metabolome profile between HCV-infected patients with CTP class B (CTP-B, significant functional compromise) and patients with CTP class A (CTP-A, well-compensated cirrhosis). MethodsWe conducted a cross-sectional study in patients with advanced HCV-related cirrhosis (n = 88) stratified by CTP-B and CTP-A. Bacterial 16S rRNA sequencing was sequenced by MiSeq Illumina technology and non-targeted metabolomics was performed by GC-MS and LC-MS ESI+ and ESI- to complement the analysis. ResultsPatients with CTP-B had lower levels of richness (Chao1), and alpha diversity (Shannon and Simpson indexes) at phylum level than patients with CTP-A. Likewise, we observed significant differences in beta diversity between groups at phylum, class, and order levels, showing lower diversity in patients with CTP-B. Higher relative abundance of Proteobacteria (p = 0.012), Alphaproteobacteria (p = 0.005), Sphingomonadales (p = 0.012) and Sphingomonadaceae (p = 0.016) were significantly associated with CTP-B. The phylum Proteobacteria was positively correlated with ethanolamine and oleic acid (p = 0.005 and p = 0.004, respectively) and negatively with p-cresol (p = 0.006). In addition, the order Sphingomonadales and the family Sphingomonadaceae was also negatively correlated with p-cresol (p = 0.001 and p = 0.001). ConclusionsBlood microbial diversity was significantly decreased in patients with CTP-B, who presented an enrichment of Proteobacteria, Alphaproteobacteria, Sphingomonadales and Sphingomonadaceae compared to patients with CTP-A.

Clinical Implications of Inflammation in Patients With Cirrhosis.

Cirrhosis-associated immune dysfunction refers to the concurrent systemic inflammation and immunoparesis evident across the disease spectrum of chronic liver disease, ranging from the low-grade inflammatory plasma milieu that accompanies compensated disease to the intense high-grade inflammatory state with coexistent severe immune paralysis that defines acute decompensation and acute-on-chronic liver failure. Systemic inflammation plays a crucial role in the disease course of cirrhosis and is a key driver for acute decompensation and the progression from compensated to decompensated cirrhosis. Severe systemic inflammation is fundamental to the development of organ dysfunction and failure and, in its most extreme form, acute-on-chronic liver failure. Systemic inflammation propagates the development of hepatic encephalopathy and hepatorenal syndrome-acute kidney injury. It may also be involved in the pathogenesis of further complications such as hepatocellular carcinoma and mental illness. Those patients with the most profound systemic inflammation have the worst prognosis. Systemic inflammation exerts its negative clinical effects through a number of mechanisms including nitric oxide-mediated increased splanchnic vasodilation, immunopathology, and metabolic reallocation.

Systematic review and meta-analysis of biomarkers predicting decompensation in patients with compensated cirrhosis

Background and aimsThe transition from compensated to decompensated cirrhosis is crucial, drastically reducing prognosis from a median survival of over 10 years to 2 years. There is currently an unmet...

Palmitoylcarnitine impairs immunity in decompensated cirrhosis

Palmitoylcarnitine impairs immunity in decompensated cirrhosis

A Brief Intervention on Alcohol Use Disorder Is Associated With Treatment Access for Inpatients With Alcohol-Associated Liver Disease.

Alcohol-associated liver disease (ALD) is the most common indication for liver transplantation in the United States. Alcohol use disorder (AUD) treatment is recommended in all patients with ALD and AUD, but it remains underutilized. To identify predictors of AUD treatment and to assess 30-day readmission, return to drinking, and 1-year transplant-free survival. Retrospective single-center cohort study of consecutive patients hospitalized with ALD and AUD between 2018 and 2020. Patients who died or were lost to follow-up at 90 days after hospitalization were excluded. AUD treatment was defined as receiving medication or participating in residential, outpatient, or support groups within 90 days of discharge. One hundred nine patients were included. Mean age was 51.7 years, and 63% were male. Fifty-six (51%) patients received AUD treatment, and 23 (21%) patients received more than one treatment. Predictors of AUD treatment were younger age (OR, 1.07 [95% CI, 1.04-1.12]; P < 0.001), gastroenterology/hepatology consult (AOR, 8.54 [95% CI, 2.55-39.50]; P = 0.0002), addiction psychiatry consult (AOR, 2.77 [95% CI, 1.16-6.84]; P = 0.02), and a brief AUD intervention (AOR, 18.19 [95% CI, 3.36-339.07]; P = 0.0001). Cirrhosis decompensation, MELD-Na score, and insurance status were not associated with treatment. Thirty-one patients (28.4%) were readmitted, and 29 (26.6%) remained abstinent 30 days from discharge. Patients who received treatment had improved transplant-free survival (HR, 0.44, P = 0.04). A brief intervention on AUD had the strongest association with receiving AUD treatment in our cohort. Further efforts to incorporate brief interventions when offering AUD treatment to patients with ALD may be beneficial.

Effect of Saccharomyces boulardii on Liver Diseases: A Systematic Review.

We aimed to systematize the results of published studies on the use of Saccharomyces boulardii (SB) for the treatment of various liver disorders (CRD42022378050). Searches were conducted using PubMed and Scopus on 1 August 2022. The PubMed search was updated on 15 June 2024. The review included sixteen studies: ten experimental animal studies (EASs) and six randomized controlled trials (RCTs). The CNCM I-745 strain was used in 68.8% of the included studies. SB reduced the severity of many manifestations of cirrhosis, and lowered the Child-Pugh scores in RCT. SB reduced the serum concentrations of TNF-α, IL-1β, IL-6, and IL-4 in animals with metabolic dysfunction-associated steatotic liver disease (MASLD); lowered the serum TNF-α and IL-6 levels in experimental cirrhosis in rats; and reduced the CRP levels in decompensated cirrhosis. The EAS of MASLD revealed that SB reduced liver steatosis and inflammation and lowered the liver expression of genes of TNF-α, IL-1β, interferon-γ, and IL-10. In studies on experimental cirrhosis and MASLD, SB reduced the liver expression of genes of TGF-β, α-SMA, and collagen as well as liver fibrosis. SB reduced the abundance of Escherichia (Proteobacteria), increased the abundance of Bacteroidetes in the gut microbiota, prevented an increase in intestinal barrier permeability, and reduced bacterial translocation and endotoxemia.

Insulin-like Growth Factor-1 Levels Reflect Muscle and Bone Health and Determine Complications and Mortality in Decompensated Cirrhosis

The growth hormone-insulin-like growth factor (GH-IGF-1) axis and its impairment with sarcopenia, frailty, bone health, complications, and prognosis are not well characterized in cirrhosis. We investigated the adult decompensated cirrhosis out-patients at a tertiary care institute between 2021 and 2023 for serum GH and IGF-1 levels, and associated them with sarcopenia (CT-SMI in cm2/m2), liver frailty index (LFI), osteodystrophy (DEXA), clinical decompensations (overall, ascites, encephalopathy, infection, and bleed), and survival up to 180 days. One-hundred-seventy-two patients, 95% males, aged 46.5 years (median). logIGF-1 levels were negatively associated with sarcopenia, osteodystrophy, LFI, CTP, and MELD-Na score (P<0.05 each). Patients with low IGF-1 levels had a higher incidence of complications (overall, ascites and encephalopathy) than those with intermediate, and high IGF-1 levels (P<0.05 each). Both logIGF-1 (AUC: 0.686) and MELD (AUC: 0.690) could predict 180-day mortality (P<0.05, each). Adding logIGF-1 with MELDNa further improved discriminative accuracy of MELDNa (AUC: 0.729) P<0.001. The increase in IGF-1 on follow-up was associated with better survival and fewer complications. Reduced IGF-1 levels reflect sarcopenia, frailty, and osteodystrophy in cirrhosis. Low IGF-1 are associated with severity, development of decompensations, and mortality.

Rejuvenating bone marrow hematopoietic reserve prevents regeneration failure and hepatic decompensation in animal model of cirrhosis.

Bone marrow stem cells (BM-SCs) and their progeny play a central role in tissue repair and regeneration. In patients with chronic liver failure, bone marrow (BM) reserve is severally compromised and they showed marked defects in the resolution of injury and infection, leading to liver failure and the onset of decompensation. Whether BM failure is the cause or consequence of liver failure during cirrhosis is not known. In this study, we aimed to determine the underlying relationship between BM failure and regeneration failure in cirrhosis. C57Bl/6(J) mice were used to develop chronic liver injury through intra-peritoneal administration of carbon tetrachloride (CCl4) for 15 weeks (0.1-0.5 ml/kg). Animals were sacrificed to study the transition of cirrhosis and BM defects. To restore the BM-SC reserve; healthy BM cells were infused via intra-BM infusion and assessed for changes in liver injury, regeneration, and BM-SC reserve. Using a CCl4-induced animal - model of cirrhosis, we showed the loss of BM-SCs reserve occurred before regeneration failure and the onset of non-acute decompensation. Intra-BM infusion of healthy BM cells induced the repopulation of native hematopoietic stem cells (HSCs) in cirrhotic BM. Restoring BM-HSCs reserve augments liver macrophage-mediated clearance of infection and inflammation dampens neutrophil-mediated inflammation, accelerates fibrosis regression, enhances hepatocyte proliferation, and delays the onset of non-acute decompensation. These findings suggest that loss of BM-HSCs reserve underlies the compromised innate immune function of the liver, drives regeneration failure, and the onset of non-acute decompensation. We further provide the proof-of-concept that rejuvenating BM-HSC reserve can serve as a potential therapeutic approach for preventing regeneration failure and transition to decompensated cirrhosis.

Prevalence and prognosis of relative aenal insufficiency in patients presenting with acute decompensation of liver cirrhosis and hyponatremia: A Prospective Cohort Study

Prevalence and prognosis of relative aenal insufficiency in patients presenting with acute decompensation of liver cirrhosis and hyponatremia: A Prospective Cohort Study

Albumin reprograms the B cell transcriptional landscape and improves neutrophil antimicrobial function in patients with decompensated cirrhosis

Background&AimPatients with acutely decompensated (AD) cirrhosis are immunocompromised and particularly susceptible to infections. This study investigated the immunomodulatory actions of albumin by which this protein may lower the incidence of infections. MethodsBlood immunophenotyping was performed in 11 AD patients and 10 healthy volunteers (HV). Bulk and single-cell (sc) RNA sequencing (RNA-seq) and flow cytometry were performed in peripheral blood mononuclear cells (PBMCs) from 20 AD patients and 34 HV exposed to albumin. Albumin’s effects on degranulation, phagocytosis, chemotaxis, and swarming of neutrophils from 6 AD patients and 9 HV were assessed by myeloperoxidase enzymatic activity, engulfment of fluorescent-labeled Escherichia coli and zymosan and interactions at single-cell resolution of neutrophils with Candida albicans in microfluidic chambers, respectively. Whole blood RNA-seq analyses were performed in 45 patients admitted for severe AD of whom 30 received albumin during hospitalization. ResultsCompared to HV, AD patients showed severe lymphopenia and defective neutrophil anti-microbial function. Bulk and scRNA-seq analyses revealed significantly (false discovery rate (FDR)<0.05) increased signatures related to B cells, myeloid cells and CD4+ T cells in PBMCs incubated with albumin. Changes in the B cell population were confirmed by flow cytometry. Neutrophils exposed to albumin also exhibited augmented chemotactic and degranulation responses, enhanced phagocytosis, and increased pathogen-restrictive swarming. Analysis of RNA-seq data in patients who had received albumin revealed specific upregulation of signatures related to B cells and neutrophils together with transcriptional changes in CD4+ T cells (FDR<0.05). ConclusionsThe finding that albumin promotes the transcriptional reprogramming and expansion of the B cell compartment and improves neutrophil antimicrobial functions indicates mechanisms that may lower the incidence of infections in patients with severe AD receiving albumin therapy.

Liver dysfunction and systemic inflammation drives organ failures among hospitalized patients with acute decompensation of cirrhosis: a multi-centric study

Liver dysfunction and systemic inflammation drives organ failures among hospitalized patients with acute decompensation of cirrhosis: a multi-centric study

Efficacy and safety of terlipressin versus octreotide with midodrine in decompensated cirrhosis patients with hepatorenal syndrome-acute kidney injury

Efficacy and safety of terlipressin versus octreotide with midodrine in decompensated cirrhosis patients with hepatorenal syndrome-acute kidney injury

Long-Term Continuous Terlipressin Infusion Improves Cardiac Reserve in Patients With Decompensated Cirrhosis

Cardiac dysfunction is a key factor in the pathogenesis of hepatorenal syndrome, for which terlipressin is the recommended first-line treatment. This study investigates whether long-term terlipressin can ameliorate the subclinical cardiac dysfunction observed in decompensated cirrhosis. Twenty-two patients with decompensated cirrhosis and ascites enrolled in a prospective study of home continuous terlipressin infusion were included. Cardiac function was assessed using dobutamine stress echocardiogram before and after 12 weeks of terlipressin. The primary outcome was the impact of terlipressin on cardiac reserve; the change in cardiac output (CO) in response to stress. Median age was 61 years (IQR 56-64), median MELD score was 15 (IQR 12.3-17.0) and 72.7% were male. The increase in CO in response to low-dose dobutamine was significantly higher following terlipressin (↑4.0L/min [↑57.8%]) as compared to baseline (↑1.8L/min [21.3%], p=0.0001). The proportion of patients with impaired cardiac reserve (defined by ΔCO <25% after low-dose dobutamine) reduced from 81.8% at baseline to 40.9% after terlipressin, (p=0.02), driven primarily by improvement in inotropic function. Resting cardiac output (CO) decreased significantly after terlipressin from 8.9±2.2L/min to 7.2±1.8 L/min (p<0.001, normal range 5-6L/min), due to a decrease in stroke volume from 108 to 86mL/beat (p=0.006). Long-term continuous terlipressin infusion resulted in a significant increase in cardiac reserve and attenuation of the hyperdynamic state usually observed in decompensated cirrhosis. These data provide important mechanistic insight into the pathogenesis and reversibility of cardiac dysfunction in cirrhosis. Future studies are required to evaluate whether long-term terlipressin can prevent hepatic decompensating events such as hepatorenal syndrome in high-risk individuals. ANZCTR NUMBER: (http://www.anzctr.org.au/): ACTRN12619000891123.

Recompensation of Chronic Hepatitis C-related decompensated cirrhosis following direct-acting antiviral therapy: Prospective Cohort study from an HCV elimination program.

Background and AimsChronic hepatitis C(CHC) related decompensated cirrhosis is associated with lower SVR-12 rates and variable regression of disease severity following direct-acting antiviral agents (DAAs). We assessed rates of SVR-12, recompensation (Baveno VII criteria), and survival in such patients. MethodsBetween July 2018-July 2023, patients with decompensated CHC-related cirrhosis post DAAs treatment, were evaluated for SVR-12 and then had 6-monthly follow-up. ResultsOf 6516 patients with cirrhosis, 1152 with decompensated cirrhosis (age 53.2±11.5 years,63% men, MELD-Na:16.5± 4.6,87% genotype 3) were enrolled. SVR-12 was 81.8% after one course; ultimately SVR was 90.8% following additional treatment. Decompensation events included ascites (1098,95.3%), hepatic encephalopathy (191,16.6%), and variceal bleeding (284,24.7%). Ascites resolved in 86% (diuretic withdrawal achieved in 24% patients). Recompensation occurred in 284(24.7%) at a median time of 16.5(IQR-14.5-20.5) months. On multivariable Cox proportional hazards analysis, low bilirubin(aHR-0.6,95%CI-0.5-0.8,P<0.001), INR(aHR-0.2,95%CI:0.1-0.3,P<0.001), absence of large esophageal varices(aHR-0.4,95%CI:0.2-0.9,P=0.048), or gastric varices (aHR-0.5,95%CI:0.3-0.7,P=0.022) predicted recompensation. Portal hypertension (PHT) progressed in 158(13.7%) patients, with rebleed in 4%. Prior decompensation with variceal bleeding (aHR-1.6,95%CI:1.2-2.8, P=0.042), and presence of large varices (aHR-2.9,95%CI:1.3-6.5,P<0.001) were associated with PHT progression. Further decompensation was seen in 221(19%);145 patients died and 6 underwent liver transplant. A decrease in MELDNa of ≥3 was in 409(35.5%) and a final MELDNa score of <10 was in 335(29%), but 2.9% developed HCC despite SVR-12. ConclusionsSVR-12 in HCV-related decompensated cirrhosis in a predominant genotype 3 population, led to recompensation in 24.7% of patients over a follow-up of 4 years in a public health setting. Despite SVR-12, new hepatic decompensation evolved in 19% and HCC developed in 2.9% of patients.

Design, implementation, and impact of a cirrhosis-specific remote patient monitoring program.

Remote patient monitoring (RPM) is an emerging focus in health care, and specialized programs may reduce medical costs, supplement in-office visits, and improve patient satisfaction. In this study, we describe the development, feasibility, and early outcomes of an RPM program for patients with decompensated cirrhosis. Forty-six patients were offered enrollment at the time of hospital discharge in the cirrhosis RPM program (CiRPM), of which 41 completed at least 30 days of monitoring. Participants were mailed remote monitoring equipment and a tablet to be used for patient-reported outcomes. Alerts were continuously monitored by virtual nursing staff who could perform targeted interventions. A cohort of historical controls (n = 74) was created for comparison using inverse probability of treatment weighting. Patients were enrolled in the program for a mean of 83.9 days, with 28 (68%) completing the full 90-day program. Participants uploaded vital signs and responded to symptom-based questionnaires on 93% of the monitored days. On end-of-program surveys, over 75% of patients expressed satisfaction with the program. Gender, age, and MELD-Na were similar between CiRPM and weighted control groups. The 90-day readmission rate was 34% in CiRPM and 47% in weighted controls. In the CiRPM group, 12% of subjects had 2 or more admissions, compared to 37% in the weighted control group. This study demonstrates the feasibility of a cirrhosis-specific RPM program. Overall, patient satisfaction and utilization of the CiRPM was high. Future studies are needed to confirm the impact of RPM on the reduction of hospital readmissions in decompensated cirrhosis.

Coagulation disorders in liver cirrhosis - Diagnostics and management

Patients with liver cirrhosis often exhibit complex alterations in their hemostatic system that can be associated with both bleeding and thrombotic complications. While prophylactic correction of abnormal coagulation parameters should be avoided, an individualized approach is recommended prior to invasive procedures, whereby specific preventive measures to stabilize hemostasis should be based on the periprocedural bleeding risk. While the haemostatic system of patients with compensated cirrhosis is often in a rebalanced haemostatic state due to a parallel decline in both pro- and anti-haemostatic factors, a decompensation of liver cirrhosis can lead to destabilization of this fragile equilibrium. Since conventional coagulation tests do not adequately capture the complex changes in the hemostatic system in cirrhosis, functional analysis methods such as viscoelastic tests or thrombin generation assays can be used for evaluating the coagulation status. This review describes the underlying pathophysiological changes in the hemostatic system in liver cirrhosis, provides an overview of diagnostic methods and discusses therapeutic measures in case of bleeding and thrombotic complications.

A clinical-radiomics nomogram for the prediction of the risk of upper gastrointestinal bleeding in patients with decompensated cirrhosis.

To develop a model that integrates radiomics features and clinical factors to predict upper gastrointestinal bleeding (UGIB) in patients with decompensated cirrhosis. 104 decompensated cirrhosis patients with UGIB and 104 decompensated cirrhosis patients without UGIB were randomized according to a 7:3 ratio into a training cohort (n = 145) and a validation cohort (n = 63). Radiomics features of the abdominal skeletal muscle area (SMA) were extracted from the cross-sectional image at the largest level of the third lumbar vertebrae (L3) on the abdominal unenhanced multi-detector computer tomography (MDCT) images. Clinical-radiomics nomogram were constructed by combining a radiomics signature (Rad score) with clinical independent risk factors associated with UGIB. Nomogram performance was evaluated in calibration, discrimination, and clinical utility. The radiomics signature was built using 11 features. Plasma prothrombin time (PT), sarcopenia, and Rad score were independent predictors of the risk of UGIB in patients with decompensated cirrhosis. The clinical-radiomics nomogram performed well in both the training cohort (AUC, 0.902; 95% CI, 0.850-0.954) and the validation cohort (AUC, 0.858; 95% CI, 0.762-0.953) compared with the clinical factor model and the radiomics model and displayed excellent calibration in the training cohort. Decision curve analysis (DCA) demonstrated that the predictive efficacy of the clinical-radiomics nomogram model was superior to that of the clinical and radiomics model. Clinical-radiomics nomogram that combines clinical factors and radiomics features has demonstrated favorable predictive effects in predicting the occurrence of UGIB in patients with decompensated cirrhosis. This helps in early diagnosis and treatment of the disease, warranting further exploration and research.

Comparative Efficacy of Stem Cells on Chronic Decompensated Cirrhosis: A Network Meta-analysis

Comparative Efficacy of Stem Cells on Chronic Decompensated Cirrhosis: A Network Meta-analysis