Spontaneous rectus sheath hematoma as a differential diagnosis for localized abdominal swelling in chronic liver disease: A rare case report.

Key Clinical Message: Spontaneous rectus sheath hematoma is a rare complication in chronic liver disease patients. Early clinical suspicion with prompt radiological evaluation is crucial for accurate diagnosis and timely management. Abstract: Spontaneous rectus sheath hematoma can present as an acute abdomen in the emergency department. The rupture of the upper and lower epigastric arteries and their branches is the main cause of hematoma formation. Hepatic dysfunction can affect the clotting process, increasing the risk of hematoma development. Computed tomography is the preferred diagnostic tool. Most hematomas can be managed conservatively, with only a few requiring minimal intervention or surgical management. We report an uncommon instance of spontaneous rectus sheath hematoma in a patient with chronic liver disease presenting with painful abdominal distention, mimicking a hernia and initially posing a diagnostic challenge. The rectus sheath hematoma was definitively diagnosed through clinical and radiological evaluation and subsequently evacuated with successful outcomes.

Protocolized Regional Citrate Anticoagulation during Continuous Renal Replacement Therapy: A Single Center Experience.

Background: Regional citrate anticoagulation (RCA) has emerged as a treatment modality that reduces bleeding risk and filter clotting. With initial experience of using RCA with continuous renal replacement therapy (CRRT), we have formulated a working protocol based on published literature. Objective: The study aimed to evaluate the protocol for routine use of RCA during CRRT requiring anticoagulation and evaluation of filter life. Methodology: It is a single-center, open-label, prospective, non-randomized, non-interventional, single-arm, observational study conducted at a tertiary care hospital between September 2022 and July 2023. All adult patients with acute kidney injury (AKI) or hyperammonemia requiring CRRT and necessitating the use of anticoagulation were enrolled in the study. The study used Prisma Flex M100 AN 69 dialyzer on Prisma Flex (Baxter) CRRT machines during continuous venovenous hemodiafiltration (CVVHDF). The targeted CRRT dose in all the study patients was 25-30 mL/kg/hour. Based on the published literature, we have developed a working protocol (Appendix 1) for managing patients on CRRT using RCA. Results: A total of 159 patients were analyzed for the study. The median [interquartile range (IQR)] filter life using RCA was 30 (12-55) hours. Filter clotting was observed in 33.3% of patients. Citrate accumulation was present in 52.25% of patients, but no CRRT was discontinued as citrate accumulation resolved after following the corrective steps in the protocol. None of the patients had citrate toxicity. Chronic liver disease (CLD) (p ≤ 0.001) and those who were post-living donor liver transplant recipients (p = 0.004) had a statistically significant increase in citrate accumulation. Also, patients who had higher lactate at baseline (6 hours post-CRRT initiation), had a higher chance of citrate accumulation. Conclusion: Our RCA protocol provides a safe approach to regional anticoagulation during CRRT in critically ill patients. How to cite this article: Pachisia AV, Kumar GP, Harne R, Jagadeesh KN, Patel SJ, Pal D, et al. Protocolized Regional Citrate Anticoagulation during Continuous Renal Replacement Therapy: A Single Center Experience. Indian J Crit Care Med 2024;28(9):859-865.

Hyponatremia Prevalence in Decompensated Chronic Liver Disease: Insights from a Tertiary Care Hospital.

BACKGROUND: Liver cirrhosis is a prominent global contributor to mortality, and hyponatremia is a common complication in patients with decompensated chronic liver disease (DCLD). Hyponatremia is characterized by kidney impairment when eliminating solute-free water. The presence of contradictory findings in existing literature prompted this study. OBJECTIVE: The objective of this study was to determine the prevalence of hyponatremia in patients with DCLDs presenting at a tertiary care hospital. METHODOLOGY:  This six-month cross-sectional study was performed at the Allied Institute of Medical Sciences Teaching Hospital in Gujranwala, Pakistan, from January 2022 to June 2022. A total of 133 patients were selected as subjects. Researchers took blood samples from these patients and sent the samples to the hospital pathology lab for evaluation of serum sodium levels. If sodium levels were ≤130 mmol/L, the patient was considered to have hyponatremia. All information was recorded on proforma. RESULTS:  The mean age of patients was 47.68 ± 12.89 years. Overall, 80 (60.15%) were male, and 53 (39.85%) female. The mean BMI of patients was 23.20 ± 3.11 kg/m2 and the average duration of DCLD was 7.24 ± 4.12 years. Among participants, 48 (36.09%) patients had hyponatremia, whereas 85 (63.91%) did not have hyponatremia. The mean sodium level was 132.39 ± 11.37 mEq/L. Stratified analysis based on patient age revealed that among patients aged 21-45 years, 27 (45.8%) had hyponatremia, whereas, in the group aged 46-70 years, 21 (28.4%) had hyponatremia with a p-value < 0.05. Stratification of the basis of BMI, among underweight patients, all eight (100%) had hyponatremia, whereas of overweight patients, 14 (31.1%) had hyponatremia. This difference was statistically significant (p < 0.05). CONCLUSION: The prevalence of hyponatremia was notably elevated among individuals suffering from DCLD. Age and BMI were the most common risk factors for hyponatremia among subjects with DCLD. This study recommends that patients with DCLD should have their serum sodium levels screened at regular intervals to prevent complications, including encephalopathy, which occurs particularly in younger and underweight DCLD patients.

Screening for compensated advanced chronic liver disease using transient elastography in outpatient addiction clinics.

BACKGROUND: Patients with substance use disorders present with many risk factors for liver disease-including alcohol, hepatitis C virus infection, and obesity-and should thus be screened for compensated advanced chronic liver disease (cACLD). Such screening could potentially be performed by outpatient addiction clinics. In this study, we aimed to assess the feasibility, acceptability, and results of cACLD screening using transient elastography (TE) among all patients attending routine follow-up visits at addiction clinics, regardless of their liver disease risk factors. METHODS: Liver fibrosis evaluation using TE was offered to every patient consulting two different addiction clinics in France, between December 2020 and September 2021, during dedicated half-day screening sessions. The screening was proposed during the patient's routine care and was performed immediately after the scheduled consultation. Patients with a liver stiffness measurement over 8 kPa were referred to a hepatology visit in the addiction clinic within 2-4 weeks. RESULTS: Screening was offered to 227 patients and was accepted by 116 (51%) patients. Twelve patients had a liver stiffness over 8 kPa, and nine of these patients attended the recommended specialist hepatology visit. Five patients (4.3% of those screened) were diagnosed with cACLD. Patients' acceptance of the screening was associated with older age, being on one's own or professionally inactive, and presenting with alcohol use disorder. CONCLUSION: Overall, our results demonstrated that opportunistic cACLD screening using TE in outpatient addiction clinics was feasible and acceptable, with good results.

Reduced muscle mass is an important part of Global Leadership Initiative on Malnutrition criteria in nutritional diagnosis of hepatocellular carcinoma.

BACKGROUND: The Global Leadership Initiative on Malnutrition criteria (GLIM) was established to build a global consensus on the diagnostic criteria for malnutrition. The study aimed to assess the prevalence of the malnutrition diagnosed by GLIM criteria for patients with hepatocellular carcinoma (HCC), and to determine the role of the reduced muscle mass defined by CT scans in the GLIM criteria. METHODS: This cohort research was conducted on adult cirrhotic patients with HCC. The risk of malnutrition was screened by Nutritional Risk Screening 2002 (NRS-2002), and malnutrition was diagnosed by GLIM criteria. The third lumbar vertebrae (L3-SMI) were used to represent the muscle mass in GLIM criteria. The variables associated with overall mortality were assessed by multivariate Cox regression analyses. RESULTS: The incidence of malnutrition diagnosed by GLIM criteria was 49.7% (179/360) in patients with HCC. If reduced muscle mass was not included in GLIM criteria, the prevalence of malnutrition was 31.7% (114/360). GLIM-defined malnutrition (HR = 1.979, 95%CI 1.019-3.841, P = 0.044) was independently associated with overall mortality in patients with HCC. However, the GLIM-defined malnutrition (without muscle mass) was not associated with overall mortality (HR = 0.863, 95%CI 0.399-1.867, P = 0.709). CONCLUSIONS: Skeletal muscle mass is an integral component of the GLIM criteria for patients with HCC. The malnutrition is common in patients with HCC, and malnourishment is associated with higher overall mortality. GLIM criteria are recommended to assess the nutritional status of hospitalized patients with HCC, which is recommended and can be used as the basis for nutritional interventions.

Tryambak Mahadev Gogate (1913-1998): A Pioneer of Panchakarma Therapies of Ayurveda.

Tryambak Mahadev Gogate (1913-1998) was instrumental in the development of practical applications of Panchakarma therapies as well as in advancing Ayurvedic education and practice, which faced significant challenges during the colonial period in India. A gifted young individual, motivated by a desire to contribute to his nation, dedicated himself to the revitalization of Ayurveda. In pursuit of this goal, he engaged in self-experimentation, often at great personal risk. He meticulously documented his findings throughout these experiments, establishing techniques for administering Panchakarma therapies, refining Ayurvedic diagnostic methods, and contributing to the evolution of Ayurveda as a scientific discipline, all while making detailed observations that paralleled advancements in modern medical science.

Interpreting elevated liver blood test results through a genetic lens: A genome-wide association study.

BACKGROUND AND AIMS: Individuals with genetic polymorphisms in UGT1A1 exhibit bilirubin levels that belie their risk of liver disease (Gilbert's syndrome) but it is not known if this phenomenon extends to other common liver blood tests (LBTs). METHODS: A genome-wide association analysis of 10 LBTs was conducted using the UK biobank. Polygenic scores (PGS) were created from discordant loci (e.g. loci associated with the LBT but not associated with cirrhosis morbidity risk). Participants were assigned to a low, intermediate or high PGS for each LBT. A high PGS approximates Gilbert's syndrome (i.e. elevated LBT without an analogous increase in disease risk). The prognostic significance of an 'elevated' LBT-and how this differs by PGS-was assessed through competing risk survival analysis. RESULTS: This study included 157 005 and 166 871 participants for the discovery and validation phases, respectively. Elevated LBTs were more prevalent in the high versus low PGS group, yet the 10-year risk of cirrhosis morbidity was comparable. For example, in the low PGS group, 4.3% had an elevated gamma-glutamyltransferase (GGT) and the 10-year risk of cirrhosis morbidity was .45%. Conversely, in the high PGS group, 21.2% had an elevated GGT and the 10-year risk was .38%. Accordingly, the 10-year risk of cirrhosis morbidity for individuals with an elevated GGT was markedly different in the low vs. high group (4.2% vs. 1.2%; p < .001). Similar results were apparent for Fibrosis-4 index, total bilirubin, and platelet count. CONCLUSION: Variability in LBTs is influenced by genetic polymorphisms that have a neutral effect on disease risk. These findings have implications for interpreting elevated LBTs in clinical practice.

Role of Imaging in Screening for Hepatocellular Carcinoma.

Primary liver cancer is among the most common cancers globally. It is the sixth-most common malignancy encountered and the third-most common cause of cancer-related death. Hepatocellular carcinoma (HCC) is the most common primary liver malignancy, accounting for about 90% of primary liver cancers. The majority of HCCs occur in patients with underlying cirrhosis, which results from chronic liver diseases such as fatty liver, hepatitis B and hepatitis C infections, and chronic alcohol use, which are the leading causes. The obesity pandemic has led to an increased prevalence of nonalcoholic fatty liver disease (NAFLD), which leads to nonalcoholic steatohepatitis and could progress to cirrhosis. As HCC is among the most common cancers and occurs in the setting of chronic liver disease in most patients, screening the population at risk could help in early diagnosis and management, leading to improved survival. Screening for HCC is performed using biochemical marker testing such as α-fetoprotein (AFP) and cross-sectional imaging. It is critical to emphasize that HCC could potentially occur in patients without cirrhosis (non-cirrhotic HCC), which can account for almost 20% of all HCCs. The lack of cirrhosis can cause a delay in surveillance, which could potentially lead to diagnosis at a later stage, worsening the prognosis for such patients. In this article, we discuss the diagnosis of cirrhosis in at-risk populations with details on the different modalities available for screening HCC in patients with cirrhosis, emphasizing the role of abdominal ultrasounds, the primary imaging modality in HCC screening.

Assessing Quality of Ultrasound Attenuation Coefficient Results for Liver Fat Quantification.

BACKGROUND/OBJECTIVES: Algorithms for quantifying liver fat content based on the ultrasound attenuation coefficient (AC) are currently available; however, little is known about whether their accuracy increases by applying quality criteria such as the interquartile range-to-median ratio (IQR/M) or whether the median or average AC value should be used. METHODS: AC measurements were performed with the Aplio i800 ultrasound system using the attenuation imaging (ATI) algorithm (Canon Medical Systems, Otawara, Tochigi, Japan). Magnetic resonance imaging proton density fat fraction (MRI-PDFF) was the reference standard. The diagnostic performance of the AC median value of 5 measurements (AC-M) was compared to that of AC average value (AC-A) of 5 or 3 acquisitions and different levels of IQR/M for median values or standard deviation/average (SD/A) for average values were also analyzed. Concordance between AC-5M, AC-5A, and AC3A was evaluated with concordance correlation coefficient (CCC). RESULTS: A total of 182 individuals (94 females; mean age, 51.2y [SD: 15]) were evaluated. A total of 77 (42.3%) individuals had S0 steatosis (MRI-PDFF < 6%), 75 (41.2%) S1 (MRI-PDFF 6-17%), 10 (5.5%) S2 (MRI-PDFF 17.1-22%), and 20 (11%) S3 (MRI-PDFF ≥ 22.1%). Concordance of AC-5A and AC-3A with AC-5M was excellent (CCC: 0.99 and 0.96, respectively). The correlation with MRI-PDFF was almost perfect. Diagnostic accuracy of AC-5M, AC-5A, and AC3A was not significantly affected by different levels of IQR/M or SD/A. CONCLUSIONS: The accuracy of AC in quantifying liver fat content was not affected by reducing the number of acquisitions (from five to three), by using the mean instead of the median, or by reducing the IQR/M or SD/A to ≤5%.

Trends in the incidence and prevalence of cirrhosis in Manitoba, Canada: A population-based study (2010-2019).

INTRODUCTION AND OBJECTIVES: The burden of chronic liver disease and cirrhosis continues to increase in North America. We sought to estimate the incidence and prevalence of cirrhosis in Manitoba, Canada over time and assess changes in trends between 2010-2019. MATERIAL AND METHODS: We performed a population-based study using Manitoba administrative health care data, and two validated case-finding algorithms. Annual incidence and prevalence rates were estimated using a generalized linear model with generalized estimating equations, adjusting for age and sex. Changes in estimates were tested using linear trend regression models. RESULTS: Two algorithms estimated the number of prevalent cirrhosis to be 16,140 and 29,943 respectively. The age- and sex-adjusted incidence rates increased over the study (from 149 to 264 cases per 100,000 population in 2010, to 177 to 388 cases per 100,000 population in 2019). Cirrhosis incidence increased annually by 2-6 %, with the largest increase (6-8 % 95 % CI 7-9 %, p <0.0001) in those aged 18-44 years. Irrespective of the algorithm used, females consistently exhibited higher cirrhosis incidence and prevalence compared to males over time (P <0.0001). Prevalence demonstrated an upward trend among all age groups over time for both algorithms (P < 0.0001). CONCLUSIONS: This population-based study highlights concerning temporal trends in cirrhosis, characterized by rising annual incidence and prevalence estimates, particularly among young adults and females. These findings underscore the urgent need for comprehensive strategies that encompass prevention, early detection, and the delivery of high-quality healthcare and public health initiatives to effectively tackle this escalating health burden.

High Altitude Liver Failure: An Infrequent Trigger.

How to cite this article: Srinivasan A, Prusty BSK. High Altitude Liver Failure: An Infrequent Trigger. Indian J Crit Care Med 2024;28(10):988.

Decoding 17-Beta-hydroxysteroid Dehydrogenase 13: A Multifaceted Perspective on Its Role in Hepatic Steatosis and Associated Disorders.

Chronic liver disease (CLD) represents a significant global health burden, with hepatic steatosis-associated disorders-such as metabolic dysfunction-associated steatohepatitis (MASH), alcoholic liver disease, and hepatitis C virus infection-being major contributors. Recent genome-wide association studies have identified the rs72613567:TA variant in the 17-beta-hydroxysteroid dehydrogenase 13 (HSD17B13) gene as a protective factor against the development and progression of these conditions. In this review, we summarized the current evidence surrounding the HSD17B13 rs72613567 variant, aiming to elucidate its impact on CLD risk and outcomes, and to explore the potential mechanisms behind its hepatoprotective effects. The rs72613567:TA variant induces a splice donor site mutation, resulting in a truncated, non-functional HSD17B13 protein. Numerous studies have demonstrated that this loss-of-function mutation confers protection against the development of cirrhosis and hepatocellular carcinoma (HCC) in patients with MASH, alcoholic liver disease, and hepatitis C virus infection. Moreover, the rs72613567:TA variant has been associated with reduced liver enzyme levels and improved survival in HCC patients. Integrating this variant into genetic risk scores has shown promise in predicting the progression of fatty liver disease to cirrhosis and HCC. Furthermore, inhibiting HSD17B13 expression through RNA interference and small molecule inhibitors has emerged as a potential therapeutic strategy for MASH. However, the precise molecular mechanisms underlying the hepatoprotective effects of the HSD17B13 rs72613567 variant remain to be fully elucidated. Future research should focus on clarifying the structure-function relationship of HSD17B13 and its role in liver pathophysiology to facilitate the development of targeted therapies for CLD associated with hepatic steatosis.

A short history of sarcopenia and frailty and their impact on advanced chronic liver disease.

Sarcopenia, first introduced as a concept by I. Rosenberg in 1989, has since been extensively studied, particularly in its correlation with chronic diseases. In recent years, sarcopenia has been increasingly associated with advanced chronic liver disease, leading to a lower quality of life and poor outcomes for these patients. Studies have shown that sarcopenia has a prevalence of 33% in individuals with advanced chronic liver disease, impacting not only the patient's health but also contributing to increased healthcare costs. The prevalence of frailty in patients with advanced chronic liver disease is 27%. Given the high prevalence of sarcopenia and frailty in this population, early diagnosis and treatment are crucial to improving patient quality of life outcomes and reducing the strain on healthcare systems globally.

Diagnostic and prognostic performance of the LiverRisk score in tertiary care.

Background & Aims: The LiverRisk score has been proposed as a blood-based tool to estimate liver stiffness measurement (LSM), thereby stratifying the risk of compensated advanced chronic liver disease (cACLD, LSM ≥10 kPa) and liver-related events in patients without known chronic liver disease (CLD). We aimed to evaluate its diagnostic/prognostic performance in tertiary care. Methods: Patients referred to two hepatology outpatient clinics (cohort I, n = 5,897; cohort II, n = 1,558) were retrospectively included. Calibration/agreement of the LiverRisk score with LSM was assessed, and diagnostic accuracy for cACLD was compared with that of fibrosis-4 (FIB-4)/aspartate aminotransferase-to-platelet ratio index (APRI). The prediction of hepatic decompensation and utility of proposed cut-offs were evaluated. Results: In cohort I/II, mean age was 48.3/51.8 years, 44.2%/44.7% were female, predominant etiologies were viral hepatitis (51.8%)/metabolic dysfunction-associated steatotic liver disease (63.7%), median LSM was 6.9 (IQR 5.1-10.9)/5.8 (IQR 4.5-8.8) kPa, and 1,690 (28.7%)/322 (20.7%) patients had cACLD.Despite a moderate correlation (Pearson's r = 0.325/0.422), the LiverRisk score systematically underestimated LSM (2.93/1.80 points/kPa lower), and range of agreement was wide, especially at higher values.The diagnostic accuracy of the LiverRisk score for cACLD (area under the receiver operator characteristics curve [AUROC] 0.757/0.790) was comparable to that of FIB-4 (AUROC 0.769/0.813) and APRI (AUROC 0.747/0.765). The proposed cut-off of 10 points yielded an accuracy of 74.2%/81.2%, high specificity (91.9%/93.4%), but low negative predictive value (76.6%/84.5%, Cohen's κ = 0.260/0.327).In cohort I, 208 (3.5%) patients developed hepatic decompensation (median follow-up 4.7 years). The LiverRisk score showed a reasonable accuracy for predicting hepatic decompensation within 1-5 years (AUROC 0.778-0.832). However, it was inferior to LSM (AUROC 0.847-0.901, p <0.001) and FIB-4 (AUROC 0.898-0.913, p <0.001). Similar to the strata of other non-invasive tests, the proposed LiverRisk groups had distinct risks of hepatic decompensation. Conclusions: The LiverRisk score did not improve the diagnosis of cACLD or prediction of hepatic decompensation in the tertiary care setting. Impact and implications: The LiverRisk score has been proposed as a non-invasive tool to estimate liver stiffness measurement and thus the risk of compensated advanced chronic liver disease and liver-related events. As automatic implementation into lab reports is being discussed, the question of its applicability outside of opportunistic screening in the general population arises. In two large cohorts of patients referred to hepatology outpatient clinics, the LiverRisk score did not accurately predict liver stiffness, did not improve cACLD identification, and had a lower predictive performance for hepatic decompensation as compared with FIB-4. Although it represents a major step forward for screening patients without known liver disease in primary care, our findings indicate that the LiverRisk score does not improve patient management outside the primary care setting, that is, in cohorts with a higher pre-test probability of cACLD.

Contribution of extracellular vesicles to steatosis-related liver disease and their therapeutic potential.

Extracellular vesicles (EVs) are small particles released by many cell types in different tissues, including the liver, and transfer specific cargo molecules from originating cells to receptor cells. This process generally culminates in activation of distant cells and inflammation and progression of certain diseases. The global chronic liver disease (CLD) epidemic is estimated at 1.5 billion patients worldwide. Cirrhosis and liver cancer are the most common risk factors for CLD. However, hepatitis C and B virus infection and obesity are also highly associated with CLD. Nonetheless, the etiology of many CLD pathophysiological, cellular, and molecular events are unclear. Changes in hepatic lipid metabolism can lead to lipotoxicity events that induce EV release. Here, we aimed to present an overview of EV features, from definition to types and biogenesis, with particular focus on the molecules related to steatosis-related liver disease, diagnosis, and therapy.

Liver at crossroads: unraveling the links between obesity, chronic liver diseases, and the mysterious obesity paradox.

Obesity is a global health issue that is intricately linked to the development and progression of chronic liver disease (CLD). This bidirectional connection, coupled with the obesity paradox (OP), presents a management dilemma. The established influence of obesity on the development and progression of chronic liver disease (CLD) is surpassed by the liver's impact on the onset and advancement of obesity. Patients with CLD always experience increased energy expenditure, reduced appetite, and low protein synthesis, all of which might lead to weight loss. However, metabolic disturbances, hormonal imbalances, inflammatory signaling, immobility, drugs, and alterations in nutrient metabolism can contribute to the development and exacerbation of obesity. Despite the propagation of the OP concept, none of the guidelines has changed, recommending being overweight. Research bias and confounders might be the lifebuoy explanation. Additionally, overlooking the lethal morbidities of obesity for survival benefits full of suffering seems to be an illogical idea. Therefore, rather than endorsing an overweight status, emphasis should be placed on improving cardiorespiratory fitness and preventing sarcopenia to achieve better outcomes in patients with CLD. Accordingly, the complex interplay between obesity, CLD, and the concept of OP requires a sophisticated individualized management approach. Maximizing cardiorespiratory fitness and mitigating sarcopenia should be considered essential strategies for attaining the most favourable outcomes in patients with chronic liver disease (CLD).

Sinusoidal communication in chronic liver disease.

The liver sinusoid, mainly composed of liver sinusoidal endothelial cells, hepatic macrophages and hepatic stellate cells, shapes the hepatic vasculature and is key maintaining liver homeostasis and function. During chronic liver disease (CLD), the function of sinusoidal cells is impaired, being directly involved in the progression of liver fibrosis, cirrhosis, and main clinical complications including portal hypertension and hepatocellular carcinoma. In addition to their roles in liver diseases pathobiology, sinusoidal cells' paracrine communication or cross-talk is being studied as a mechanism of disease but also as a remarkable target for treatment. The aim of this review is to gather current knowledge of intercellular signalling in the hepatic sinusoid during the progression of liver disease. We summarise studies developed in pre-clinical models of CLD, specially emphasizing those pathways characterized in human-based clinically relevant models. Finally, we describe pharmacological treatments targeting sinusoidal communication as promising options to treat CLD and its clinical complications.

Serum Adiponectin Is Elevated in Critically Ill Patients with Liver Disease and Associated with Decreased Overall Survival.

BACKGROUND: Adiponectin, an adipokine with anti-inflammatory properties, has been implicated in various liver diseases. This study aimed to elucidate the prognostic value of serum adiponectin levels in critically ill patients with liver disease. METHODS: This observational study included 161 critically ill patients admitted to the medical ICU of RWTH Aachen University Hospital due to acute liver failure or decompensated advanced chronic liver disease. Serum adiponectin levels were measured at ICU admission and after 48 h. Clinical parameters and outcomes, including transplant-free survival, were analyzed. RESULTS: Serum adiponectin concentrations were significantly elevated compared to healthy controls (p < 0.001). Levels were particularly high in patients with sepsis compared to those with gastrointestinal bleeding as the precipitating factor of acute decompensation (p = 0.045) and were higher in female patients (p = 0.023). Adiponectin concentrations correlated with the Model of End-Stage Liver Disease (MELD) score and Child-Pugh score. Multivariate analysis confirmed a significant correlation with total bilirubin (r = 0.292, p < 0.001) and serum sodium (r = -0.265, p = 0.028). Higher adiponectin concentrations were associated with a trend towards poorer 30- and 180-day survival. Cox regression analysis identified a significant association between increased adiponectin concentration and reduced transplant-free survival (p = 0.037), supported by a Kaplan-Meier analysis using a cutoff of 119 ng/mL (log-rank 5.145, p = 0.023). CONCLUSIONS: Elevated serum adiponectin concentrations are associated with liver dysfunction and poor outcomes in critically ill patients. Higher adiponectin levels at ICU admission may predict poorer transplant-free survival. Further research in larger, multicenter cohorts is warranted to validate these findings and explore the underlying mechanisms.

ECM1 attenuates hepatic fibrosis by interfering with mediators of latent TGF-ß1 activation.

OBJECTIVE: Extracellular matrix protein 1 (ECM1) serves as a gatekeeper of hepatic fibrosis by maintaining transforming growth factor-ß1 (TGF-ß1) in its latent form. ECM1 knockout (KO) causes latent (L) TGF-ß1 activation, resulting in hepatic fibrosis with rapid mortality. In chronic liver disease (CLD), ECM1 decreases with increasing CLD severity. We investigate the regulatory role of ECM1 in TGF-ß1 bioavailability and its impact on CLD progression. DESIGN: RNAseq was performed to analyse hepatic gene expression. Functional assays were performed using hepatic stellate cells (HSCs), Ecm1-KO and Fxr-KO mice, patient liver tissue and computer simulations. RESULTS: Expression of LTGF-ß1 activators, including thrombospondins (TSPs), ADAMTS proteases and matrix metalloproteinases (MMPs), increased along with profibrotic gene expression in liver tissue of Ecm1-KO mice. In HSCs, overexpression of ECM1 prevented LTGF-ß1 activation mediated by TSP-1, ADAMTS1, and MMP-2/9. In vitro interaction assays demonstrated that ECM1 inhibited LTGF-ß1 activation by interacting with TSP-1 and ADAMTS1 via their respective, intrinsic KRFK or KTFR amino acid sequences and by suppressing MMP-2/9 proteolytic activity. In mice, ECM1 overexpression attenuated KRFK-induced LTGF-ß1 activation while KTFR treatment reversed Ecm1-KO-mediated and Fxr-KO-mediated liver injury. In patients with CLD, ECM1 expression was inversely correlated with TSP-1, ADAMTS1, MMP-2/9 expression and LTGF-ß1 activation. And, these results were complemented by a computational compartment model representing the key network of cellular phenotypes and predicted interactions in liver fibrogenesis. CONCLUSION: Our findings underscore the hepatoprotective effect of ECM1, which interferes with mediators of LTGF-ß1 activation, suggesting ECM1 or its representative peptide as potential antifibrotic therapies in CLD.