A randomized controlled trial of a postdischarge nursing intervention for patients with decompensated cirrhosis.

BACKGROUND: Few randomized trials have evaluated the effect of postdischarge interventions for patients with liver cirrhosis. This study assessed the effects of a postdischarge intervention on readmissions and mortality in patients with decompensated liver cirrhosis. METHODS: We conducted a randomized controlled trial at a specialized liver unit. Adult patients admitted with complications of liver cirrhosis were eligible for inclusion. Participants were allocated 1:1 to standard follow-up or a family-focused nurse-led postdischarge intervention between December 1, 2019, and October 31, 2021. The 6-month intervention consisted of a patient pamphlet, 3 home visits, and 3 follow-up telephone calls by a specialized liver nurse. The primary outcome was the number of readmissions due to liver cirrhosis. RESULTS: Of the 110 included participants, 93% had alcohol as a primary etiology. We found no significant differences in effects in the primary outcomes such as time to first readmission, number of patients readmitted, and duration of readmissions or in the secondary outcomes like health-related quality of life and 6- and 12-month mortality. A post hoc exploratory analysis showed a significant reduction in nonattendance rates in the intervention group (RR: 0.28, 95% CI: 0.13-0.54, p=0.0004) and significantly fewer participants continuing to consume alcohol in the intervention group (p=0.003). After 12 months, the total number of readmissions (RR: 0.76, 95% CI: 0.59-0.96, p=0.02) and liver-related readmissions (RR: 0.55, 95% CI: 0.36-0.82, p=0.003) were reduced in the intervention group. CONCLUSIONS: A family-focused postdischarge nursing intervention had no significant effects on any of the primary or secondary outcomes. In a post hoc exploratory analysis, we found reduced 6-month nonattendance and alcohol consumption rates, as well as reduced 12-month readmission rates in the intervention group.

No difference in postprandial mesenteric blood flow between healthy younger and elderly individuals.

We recently used phase-contrast magnetic resonance imaging (PC-MRI) to demonstrate an attenuated postprandial blood flow response in the superior mesenteric artery (SMA) in patients with Parkinson's disease compared to age- and sex-matched healthy controls. Since both groups showed substantial inter-individual variations, we extended the cohort of controls with a group of young individuals to investigate possible age-related effects. Seventeen healthy young subjects aged < 30 years and 17 elderly subjects aged > 50 years underwent serial PC-MRI to measure the postprandial blood flow response in the SMA after ingestion of a standardized liquid test meal (∼400 kcal). Postprandial blood flow dynamics in SMA did not differ between young and elderly subjects. A noticeable inter-individual variation in postprandial intestinal blood flow increase was found, and approximately 30% of the variation could be explained by the preprandial blood flow. Regardless of age, some subjects showed a remarkable transient SMA blood flow increase immediately after meal intake. This study provides tentative evidence that postprandial blood flow dynamics in SMA in healthy young and elderly subjects do not substantially differ, indicating that age is without impact on vascular response in SMA as an indicator for regulation of mesenteric perfusion in response to food intake.

Patients with autoimmune liver disease have glucose disturbances that mechanistically differ from steatotic liver disease.

Autoimmune liver diseases are associated with an increased risk of diabetes, yet the underlying mechanisms remain unknown. In this cross-sectional study, we investigated the glucose-regulatory disturbances in patients with autoimmune hepatitis (AIH, n=19), primary biliary cholangitis (PBC, n=15), and primary sclerosing cholangitis (PSC, n=6). Healthy individuals (n=24) and patients with metabolic dysfunction-associated steatotic liver disease (MASLD, n=18) were included as controls. Blood samples were collected during a 120 min oral glucose tolerance test. We measured the concentrations of glucose, C-peptide, insulin, glucagon, the two incretin hormones glucose insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1). We calculated the homeostasis model assessment of insulin resistance (HOMA-IR), whole body insulin resistance (Matsuda index), insulin clearance, and insulinogenic index. All patient groups had increased fasting plasma glucose and impaired glucose responses compared with healthy controls. Beta-cell secretion was increased in AIH, PBC, and MASLD but not in PSC. AIH and MASLD patients had hyperglucagonemia and hepatic, as well as peripheral, insulin resistance and decreased insulin clearance, resulting in hyperinsulinemia. Patients with autoimmune liver disease had an increased GIP response, and those with AIH or PBC had an increased GLP-1 response. Our data demonstrate that the mechanism underlying glucose disturbances in patients with autoimmune liver disease differs from that underlying MASLD, including compensatory incretin responses in patients with autoimmune liver disease. Our results suggest that glucose disturbances are present at an early stage of the disease.

Specific antibiotics increases the risk of flare-ups in patients with inflammatory bowel disease - results from a Danish nationwide population-based nested case-control study.

INTRODUCTION: IBD patients have a relapsing-remitting disease course, and amongst environmental factors that aggravate the disease course, common drugs aside from NSAIDs are not studied in detail. While the microbiome is considered to play a significant role on the disease course the impact of antibiotics is poorly understood. This study investigated the potential impact of different classes of antibiotics on course of disease in IBD using the Danish National Patient Registry. METHODS: Danish IBD patients were studied using two nested case-control cohorts exploring associations between antibiotic types and IBD flare-ups, defined as IBD-related hospitalizations and/or high-dose systemic steroid exposure. Multivariate logistic regression and eXtreme Gradient Boosted decision tree (GBDT) machine learning methods evaluated antibiotic risks. RESULTS: Two cohorts with 15,636 and 5,178 patients were analysed for risk of hospitalisation and course of steroids, respectively.The risk of a flare-up was significantly increased with antecedent exposure to quinolones (ATC:J01M. OR:3.04-3.82), antimycotics (ATC:J02A. OR:1.50-2.30), agents against amoebiasis and protozoal infections (ATC:P01A. OR: 1.95-3.18), intestinal anti-infectives (ATC:A07A. OR:2.09-2.32) and beta-lactam antibiotics (ATC:J01C. OR:1.36).The GBDT models achieved an AUC between 0.71-0.85 for predicting flare-ups, with the same above-mentioned antibiotics being in the 10 most important variables. CONCLUSION: We found distinctive antibiotics to be significantly associated with an increased risk of IBD flare-ups. Our findings are corroborated by our GBDT machine learning models. Healthcare providers should be aware about the deleterious potential of specific antibiotic groups in patients with IBD only using these agents in a restrictive manner or preferentially consider alternative antibiotic groups.

Peripheral joint and enthesis involvement in patients with newly diagnosed inflammatory bowel disease: symptoms, clinical and ultrasound findings - a population-based cohort study.

OBJECTIVES: Musculoskeletal manifestations in patients with inflammatory bowel disease (IBD) are common and associated with poorer outcomes. Hence, early detection is important to optimally tailor treatment. We aimed to determine the prevalence and distribution of inflammatory lesions in peripheral joints and entheses in newly diagnosed IBD patients. DESIGN: Patients with newly diagnosed IBD from a prospective population-based inception cohort were consecutively included. Data on musculoskeletal symptoms were collected by questionnaires and by structured rheumatological interview. Peripheral joints and entheses were assessed clinically and by ultrasound (US), using standardized definitions. RESULTS: Of 110 included patients (mean age: 42 years, 40% male, 70 with ulcerative colitis (UC), 40 with Crohn's disease (CD)), history of ≥1 musculoskeletal symptoms was reported by 49%. Clinical examination revealed peripheral musculoskeletal manifestations in 56 (52.3%) patients; 29 (27.1%) had ≥1 tender and/or swollen joints and 49 (45.8%) ≥1 tender entheses. Small peripheral joints were predominantly affected. US found inflammation in ≥1 joint or enthesis in 52 (49.5 %) patients; 29 (27.4 %) had US synovitis in ≥1 joint, while 36 (34%) US enthesitis. Fibromyalgia classification criteria were fulfilled in seven (7.9%) patients. There was no difference in clinical or US findings between patients with UC and CD, nor between patients with active and inactive IBD. CONCLUSION: Half of patients with newly diagnosed IBD had inflammation in their peripheral joints and/or entheses, documented by rheumatological clinical and ultrasound evaluations. This indicates a need for multidisciplinary collaboration to ensure an optimal therapeutic strategy for suppressing inflammation in all disease domains.

Low sphingolipid levels predict poor survival in patients with alcohol-related liver disease.

Background & Aims: Alcohol-related hepatitis (AH) and alcohol-related cirrhosis are grave conditions with poor prognoses. Altered hepatic lipid metabolism can impact disease development and varies between different alcohol-related liver diseases. Therefore, we aimed to investigate lipidomics and metabolomics at various stages of alcohol-related liver diseases and their correlation with survival. Methods: Patients with newly diagnosed alcohol-related cirrhosis, who currently used alcohol (ALC-A), stable outpatients with decompensated alcohol-related cirrhosis with at least 8 weeks of alcohol abstinence (ALC), and patients with AH, were compared with each other and with healthy controls (HC). Circulating lipids and metabolites were analysed using HPLC and mass spectrometry. Results: Forty patients with ALC, 95 with ALC-A, 30 with AH, and 42 HC provided plasma. Lipid levels changed according to disease severity, with generally lower levels in AH and cirrhosis than in the HC group; this was most pronounced for AH, followed by ALC-A. Nine out of 10 free fatty acids differed between cirrhosis groups by relative increases of 0.12-0.66 in ALC compared with the ALC-A group (p <0.0005). For metabolomics, total bile acids increased by 19.7, 31.3, and 80.4 in the ALC, ALC-A, and AH groups, respectively, compared with HC (all p <0.0001). Low sphingolipid ([d42:1] and [d41:1]) levels could not predict 180-day mortality (AUC = 0.73, p = 0.95 and AUC = 0.73, p = 0.95) more accurately than the model for end-stage liver disease score (AUC = 0.71), but did predict 90-day mortality (AUC d42:1 = 0.922, AUC d41:1 = 0.893; pd42:1 = 0.005, pd41:1 = 0.007) more accurately than the MELD score AUCMELD = 0.70, pMELD = 0.19). Conclusions: Alcohol-related severe liver disease is characterised by low lipid levels progressing with severity of liver disease, especially low sphingomyelins, which also associate to poor prognoses. Impact and implications: Lipidomics has the potential to diagnose and risk stratify patients with liver diseases. Lipidomics differed between patients with alcohol-related hepatitis and alcohol-related cirrhosis with and without recent alcohol use. Furthermore, lipidomics could predict short-term mortality and might be suitable as a prognostic tool in the future. Clinical Trials Registration: Scientific Ethics Committee of the Capital Region of Denmark, journal no. H-21013476.

Targeted metabolomics reveals plasma short-chain fatty acids are associated with metabolic dysfunction-associated steatotic liver disease.

BACKGROUND: Alterations in the production of short-chain fatty acids (SCFAs) may reflect disturbances in the gut microbiota and have been linked to metabolic dysfunction-associated steatotic liver disease (MASLD). We assessed plasma SCFAs in patients with MASLD and healthy controls. METHODS: Fasting venous blood samples were collected and eight SCFAs were measured using gas chromatography-tandem mass spectrometry (GC-MS/MS). Relative between-group differences in circulating SCFA concentrations were estimated by linear regression, and the relation between SCFA concentrations, MASLD, and fibrosis severity was investigated using logistic regression. RESULTS: The study includes 100 patients with MASLD (51% with mild/no fibrosis and 49% with significant fibrosis) and 50 healthy controls. Compared with healthy controls, MASLD patients had higher plasma concentrations of propionate (21.8%, 95% CI 3.33 to 43.6, p = 0.02), formate (21.9%, 95% CI 6.99 to 38.9, p = 0.003), valerate (35.7%, 95% CI 4.53 to 76.2, p = 0.02), and α-methylbutyrate (16.2%, 95% CI 3.66 to 30.3, p = 0.01) but lower plasma acetate concentrations (- 30.0%, 95% CI - 40.4 to - 17.9, p < 0.001). Among patients with MASLD, significant fibrosis was positively associated with propionate (p = 0.02), butyrate (p = 0.03), valerate (p = 0.03), and α-methylbutyrate (p = 0.02). Six of eight SCFAs were significantly increased in F4 fibrosis. CONCLUSIONS: In the present study, SCFAs were associated with MASLD and fibrosis severity, but further research is needed to elucidate the potential mechanisms underlying our observations and to assess the possible benefit of therapies modulating gut microbiota.

Atorvastatin for patients with cirrhosis. A randomized, placebo-controlled trial.

BACKGROUND: Patients with cirrhosis and portal hypertension face a high risk of complications. Besides their anti-inflammatory and antifibrotic effects, statins may reduce portal pressure and thus the risk of complications and mortality. We aimed to investigate the effects of atorvastatin on hospital admissions, mortality, inflammation, and lipidomics in cirrhosis with portal hypertension. METHODS: We performed a double-blinded, randomized, placebo-controlled clinical trial among patients with cirrhosis and portal hypertension. Atorvastatin (10-20 mg/d) was administered for 6 months. We measured splanchnic hemodynamics, analyzed inflammatory markers, and performed lipidomics at baseline and after 6 months. RESULTS: Seventy-eight patients were randomized, with 38 patients allocated to atorvastatin and 40 patients to placebo. Fifty-nine patients completed 6 months of intervention. Comparisons between changes in each group were calculated. Liver-related complications and mortality were similar between the groups. The HVPG and Model for End-stage Liver Disease score did not change between groups (p=0.95 and 0.87, respectively). Atorvastatin decreased 3 of 42 inflammatory markers, CD62-L-selectin, matrix metalloproteinases-2, and TNF-α (p-values: 0.005, 0.011, and 0.023, respectively), while lipidomics was not significantly changed. CONCLUSIONS: In patients with cirrhosis, atorvastatin was safe to use, but did not reduce mortality, the risk of liver-related complications, or the HVPG. Atorvastatin induced minor anti-inflammatory effects and minor effects on lipids during a 6-month treatment period.

Neprilysin activity is increased in metabolic dysfunction-associated steatotic liver disease and normalizes after bariatric surgery or GLP-1 therapy.

Inhibitors of neprilysin improve glycemia in patients with heart failure and type 2 diabetes (T2D). The effect of weight loss by diet, surgery, or pharmacotherapy on neprilysin activity (NEPa) is unknown. We investigated circulating NEPa and neprilysin protein concentrations in obesity, T2D, metabolic dysfunction-associated steatotic liver disease (MASLD), and following bariatric surgery, or GLP-1-receptor-agonist therapy. NEPa, but not neprilysin protein, was enhanced in obesity, T2D, and MASLD. Notably, MASLD associated with NEPa independently of BMI and HbA1c. NEPa decreased after bariatric surgery with a concurrent increase in OGTT-stimulated GLP-1. Diet-induced weight loss did not affect NEPa, but individuals randomized to 52-week weight maintenance with liraglutide (1.2 mg/day) decreased NEPa, consistent with another study following 6-week liraglutide (3 mg/day). A 90-min GLP-1 infusion did not alter NEPa. Thus, MASLD may drive exaggerated NEPa, and lowered NEPa following bariatric surgery or liraglutide therapy may contribute to the reported improved cardiometabolic effects.

Markers of inflammation predict survival in newly diagnosed cirrhosis: a prospective registry study.

The inflammatory activity in cirrhosis is often pronounced and related to episodes of decompensation. Systemic markers of inflammation may contain prognostic information, and we investigated their possible correlation with admissions and mortality among patients with newly diagnosed liver cirrhosis. We collected plasma samples from 149 patients with newly diagnosed (within the past 6 months) cirrhosis, and registered deaths and hospital admissions within 180 days. Ninety-two inflammatory markers were quantified and correlated with clinical variables, mortality, and admissions. Prediction models were calculated by logistic regression. We compared the disease courses of our cohort with a validation cohort of 86 patients with cirrhosis. Twenty of 92 markers of inflammation correlated significantly with mortality within 180 days (q-values of 0.00-0.044), whereas we found no significant correlations with liver-related admissions. The logistic regression models yielded AUROCs of 0.73 to 0.79 for mortality and 0.61 to 0.73 for liver-related admissions, based on a variety of modalities (clinical variables, inflammatory markers, clinical scores, or combinations thereof). The models performed moderately well in the validation cohort and were better able to predict mortality than liver-related admissions. In conclusion, markers of inflammation can be used to predict 180-day mortality in patients with newly diagnosed cirrhosis. Prediction models for newly diagnosed cirrhotic patients need further validation before implementation in clinical practice.Trial registration: NCT04422223 (and NCT03443934 for the validation cohort), and Scientific Ethics Committee No.: H-19024348.

Effect of beta-blockers on multiple haemodynamics in cirrhosis: A cross-over study by MR-imaging and hepatic vein catheterization.

BACKGROUND: Non-selective beta-blockers (NSBB) are widely used in the treatment of patients with cirrhosis. Only about 50% respond with a sufficient reduction in their hepatic venous pressure gradient (HVPG) and NSBB may induce detrimental cardiac and renal effects in the presence of severe decompensation. We aimed to assess the effects of NSBB on haemodynamics using magnetic resonance imaging (MRI) and to assess if these haemodynamic changes were related to the disease severity and HVPG response. METHOD: A prospective cross-over study of 39 patients with cirrhosis. Patients underwent hepatic vein catheterization and MRI with assessments of HVPG, cardiac function, systemic and splanchnic haemodynamics before and after propranolol infusion. RESULTS: Propranolol induced significant decreases in cardiac output (-12%) and blood flow of all vascular compartments, with the largest reductions seen in the azygos venous (-28%), portal venous (-21%), splenic (-19%) and superior mesenteric artery (-16%) blood flow. Renal artery blood flow fell by -5% in the total cohort, with a more pronounced reduction in patients without ascites than in those with ascites (-8% vs. -3%, p = .01). Twenty-four patients were NSBB responders. Their changes in HVPG after NSBB were not significantly associated with other haemodynamic changes. CONCLUSION: The changes in cardiac, systemic and splanchnic haemodynamics did not differ between NSBB responders and non-responders. The effects of acute NSBB blockade on renal flow seem to depend on the severity of the hyperdynamic state, with the largest reduction in renal blood flow in compensated patients compared to decompensated patients with cirrhosis. However, future studies are needed to assess the effects of NSBB on haemodynamics and renal blood flow in patients with diuretic-resistant ascites.

Beta-adrenergic blockade in cirrhosis - harmful or helpful?

INTRODUCTION: Portal hypertension exacerbates the disease course of cirrhosis and is responsible for major complications, including bleeding from esophageal varices, ascites, and encephalopathy. More than 40 years ago, Lebrec and colleagues introduced beta-blockers to prevent esophageal bleeding. However, evidence now suggests that beta-blockers may cause adverse reactions in patients with advanced cirrhosis. AREAS COVERED: This review addresses current evidence for the pathophysiology of portal hypertension, focusing on the pharmacological effects of treatment with beta-blockers, indications for preventing variceal bleeding, their effects on decompensated cirrhosis, and the risk of treating patients suffering from decompensated ascites and renal dysfunction with beta-blockers. EXPERT OPINION: The diagnosis of portal hypertension should be based on direct measurements of portal pressure. Carvedilol or nonselective beta-blockers are the first-line treatment for patients with medium-to-large varices as primary or secondary prophylaxis, in Child C patients with small varices, and sometimes for patients with clinically significant portal hypertension (HVPG ≥ 10 mm Hg, irrespective of the presence of varices) to prevent decompensation. Caution should be used when treating decompensated patients who are suspected of imminent cardiac and renal dysfunction. Future strategies for managing patients with portal hypertension should aim for more personalized treatment that takes into account the disease stage.

Altered serum bile acid composition is associated with cardiac dysfunction in cirrhosis.

BACKGROUND: Elevated serum bile acids (BA) are harmful to the heart and alterations in the BA composition have been suggested to cause cardiovascular disturbances in cirrhosis. AIM: To investigate any associations between specific groups or individual serum BA and structural and functional cardiac abnormalities in patients with cirrhosis. METHODS: An explorative study in 86 patients with cirrhosis. All participants underwent extensive cardiac assessment, including cardiac MRI with quantification of myocardial extracellular volume (ECV), which is indicative of diffuse myocardial fibrosis. A panel of 15 individual serum BA and C4, a marker of de novo bile acid synthesis, were assessed. RESULTS: Patients with advanced cirrhosis had higher levels of total BA and conjugated BA, as well as lower C4 levels (p < 0.001). Conjugated BA levels were higher in patients with a high cardiac index (p < 0.001), increased left atrial volume index (LAVI) (p < 0.001), and in those with an abnormal myocardial ECV (p < 0.05). We also found several strong correlations between conjugated BA, both as a group and individually, and parameters of cardiac dysfunction. In a model adjusted for sex, age, BMI and MELD, conjugated BA remained significantly associated with LAVI, septal e', left ventricular volumes and cardiac index. In addition, taurocholic acid correlated closely with hepatic venous pressure gradient (HVPG) (p = 0.01). CONCLUSIONS: Increased serum concentrations of conjugated BA are associated with several cardiac parameters, indicating a potential role in the development of hyperdynamic circulation and cardiac dysfunction in cirrhosis. Moreover, taurine-conjugated BA are associated with portal hypertension.

Nurse-assisted and multidisciplinary outpatient follow-up among patients with decompensated liver cirrhosis: A systematic review.

BACKGROUND AND OBJECTIVE: Liver cirrhosis represents a considerable health burden and causes 1.2 million deaths annually. Patients with decompensated liver cirrhosis have a poor prognosis and severely reduced health-related quality of life. Nurse-led outpatient care has proven safe and feasible for several chronic diseases and engaging nurses in the outpatient care of patients with liver cirrhosis has been recommended. At the decompensated stage, the treatment and nursing care are directed at specific complications, educational support, and guidance concerning preventive measures and signs of decompensation. This review aimed to assess the effects of nurse-assisted follow-up after admission with decompensation in patients with liver cirrhosis from all causes. METHOD: A systematic search was conducted through February 2022. Studies were eligible for inclusion if i) they assessed adult patients diagnosed with liver cirrhosis that had been admitted with one or more complications to liver cirrhosis and ii) if nurse-assisted follow-up, including nurse-assisted multidisciplinary interventions, was described in the manuscript. Randomized clinical trials were prioritized, but controlled trials and prospective cohort studies with the intervention were also included. Primary outcomes were mortality and readmission, but secondary subjective outcomes were also assessed. RESULTS AND CONCLUSION: We included eleven controlled studies and five prospective studies with a historical control group comprising 1224 participants. Overall, the studies were of moderate to low quality, and heterogeneity across studies was substantial. In a descriptive summary, the 16 studies were divided into three main types of interventions: educational interventions, case management, and standardized hospital follow-up. We saw a significant improvement across all types of studies on several parameters, but currently, no data support a specific type of nurse-assisted, post-discharge intervention. Controlled trials with a predefined intervention evaluating clinically- and practice-relevant endpoints in a real-life, patient-oriented setting are highly warranted.

Disease Activity Patterns of Inflammatory Bowel Disease-A Danish Nationwide Cohort Study 1995-2018.

BACKGROUND AND AIMS: Few studies have assessed the contemporary patterns of disease activity in patients with inflammatory bowel disease [IBD]. We aimed to describe the disease patterns and their long-term outcomes. METHODS: All Danish individuals with IBD between 1995 and 2018 were identified using information about IBD-related hospitalizations, surgeries and redeemed prescriptions. The disease activity patterns for 5- and 10-year periods were assessed. RESULTS: In incident patients with Crohn's disease [CD], severe disease activity occurred in the year of diagnosis in 80% of patients; for ulcerative colitis [UC] this figure was 75%, in addition to 3.4% of UC patients who underwent a colectomy within the first year. After 20 years of disease, the proportion of CD and UC patients in remission increased to 89% and 72%, respectively. The proportion of prevalent patients in remission each year was stable, despite the introduction of biological therapies. A decreasing activity pattern was the most common in both CD and UC patients [both 45%]. The distribution of the disease activity patterns was seen to be stable over time. A quiescent disease pattern was accompanied by a significantly higher risk of intestinal cancer [HR: 3.37, 95% CI: 1.23-9.19] for CD patients, according to a Cox proportional hazards model. In UC patients, increasing disease activity [HR: 0.67, 95% CI: 0.31-1.48] was associated with an increased risk of intestinal cancer. CONCLUSIONS: We report the distribution of disease patterns among IBD patients. Patients with quiescent CD, as well as UC patients with chronic continuous or increasing activity, were at increased risk of developing intestinal cancer.

Assessment of portal hypertension severity using machine learning models in patients with compensated cirrhosis.

BACKGROUND & AIMS: In individuals with compensated advanced chronic liver disease (cACLD), the severity of portal hypertension (PH) determines the risk of decompensation. Invasive measurement of the hepatic venous pressure gradient (HVPG) is the diagnostic gold standard for PH. We evaluated the utility of machine learning models (MLMs) based on standard laboratory parameters to predict the severity of PH in individuals with cACLD. METHODS: A detailed laboratory workup of individuals with cACLD recruited from the Vienna cohort (NCT03267615) was utilised to predict clinically significant portal hypertension (CSPH, i.e., HVPG ≥10 mmHg) and severe PH (i.e., HVPG ≥16 mmHg). The MLMs were then evaluated in individual external datasets and optimised in the merged cohort. RESULTS: Among 1,232 participants with cACLD, the prevalence of CSPH/severe PH was similar in the Vienna (n = 163, 67.4%/35.0%) and validation (n = 1,069, 70.3%/34.7%) cohorts. The MLMs were based on 3 (3P: platelet count, bilirubin, international normalised ratio) or 5 (5P: +cholinesterase, +gamma-glutamyl transferase, +activated partial thromboplastin time replacing international normalised ratio) laboratory parameters. The MLMs performed robustly in the Vienna cohort. 5P-MLM had the best AUCs for CSPH (0.813) and severe PH (0.887) and compared favourably to liver stiffness measurement (AUC: 0.808). Their performance in external validation datasets was heterogeneous (AUCs: 0.589-0.887). Training on the merged cohort optimised model performance for CSPH (AUCs for 3P and 5P: 0.775 and 0.789, respectively) and severe PH (0.737 and 0.828, respectively). CONCLUSIONS: Internally trained MLMs reliably predicted PH severity in the Vienna cACLD cohort but exhibited heterogeneous results on external validation. The proposed 3P/5P online tool can reliably identify individuals with CSPH or severe PH, who are thus at risk of hepatic decompensation. IMPACT AND IMPLICATIONS: We used machine learning models based on widely available laboratory parameters to develop a non-invasive model to predict the severity of portal hypertension in individuals with compensated cirrhosis, who currently require invasive measurement of hepatic venous pressure gradient. We validated our findings in a large multicentre cohort of individuals with advanced chronic liver disease (cACLD) of any cause. Finally, we provide a readily available online calculator, based on 3 (platelet count, bilirubin, international normalised ratio) or 5 (platelet count, bilirubin, activated partial thromboplastin time, gamma-glutamyltransferase, choline-esterase) widely available laboratory parameters, that clinicians can use to predict the likelihood of their patients with cACLD having clinically significant or severe portal hypertension.

Association of low mechano-energetic efficiency and prognosis in liver cirrhosis.

BACKGROUND: In cirrhosis, cardiac systolic dysfunction as part of cirrhotic cardiomyopathy affects prognosis. Myocardial mechano-energetic efficiency (MEE) is an estimate of left ventricular performance. In this study we investigated the relation of MEE to patient characteristics and its impact on survival in patients with cirrhosis. PATIENTS AND METHODS: We included 283 patients with cirrhosis of different severity according to the Child-Pugh classifications (A/B/C: 106/87/90). All patients had a liver vein catheterization and a hemodynamic investigation performed including determination of cardiac output (CO), stroke volume and heart rate (HR). These data were used to assess MEE, which was defined as (stroke volume/HR) × 1.666. RESULTS: Eighty-nine percent of patients had portal hypertension (hepatic venous pressure gradient >5 mmHg) and 80% indications of hyperdynamic circulatory state (increased CO and HR). There was no difference in MEE in Child-Pugh class C patients (2.03) versus Child-Pugh class A (1.98) and B (2.05) patients. In Child-Pugh class C patients, low MEE was associated with a poorer prognosis. CONCLUSION: In our study, MEE does not seem to be associated with severity of the liver disease, but in patients with advanced disease low MEE is associated with a poorer prognosis. The prognostic impact of MEE should be further investigated.

Biomarkers reflecting pericellular fibrosis improve together with liver histology after bariatric surgery in early non-alcoholic fatty liver disease.

AIM: Non-invasive tests for non-alcoholic fatty liver disease (NAFLD) are needed for assessing disease stage, prognosis and treatment efficacy. Extracellular matrix biomarkers, such as PRO-C3, are useful as biomarkers of advanced liver fibrosis. However, non-invasive biomarkers of early-stage NAFLD, characterized by pericellular fibrosis, are lacking. Here, we measured serological biomarkers of type IV and VIII collagens reflecting the remodeling of the pericellular basement membrane to explore the effect of bariatric surgery on pericellular fibrosis in patients with early NAFLD. METHODS: Seventy patients with severe obesity underwent bariatric surgery. The cohort consisted of 61 % females who had a mean age of 44. Patients had a median NAFLD activity score of 3 and mild-to-moderate fibrosis F0 (3 %), F1 (86 %), and F2 (11 %). Blood samples were taken at baseline, three, six and 12 months after surgery. At 12 months, 40 patients had a follow-up liver biopsy. The biomarkers PRO-C3, PRO-C4, C4M, and PRO-C8 were measured using indirect competitive ELISAs. RESULTS: Twelve months after surgery patients had significantly lower levels of ALT, GGT, HbA1c, fasting glucose, and CRP. The pericellular fibrosis biomarkers, C4M, PRO-C4, and PRO-C8 decreased by 24 %, 18 % and 44 %, respectively (p < 0.0001), while the interstitial matrix fibrosis marker PRO-C3 remained unchanged. Furthermore, baseline C4M was associated with histologically assessed hepatocyte ballooning and lobular inflammation in patients with (p = 0.032) and without (p = 0.032) steatosis, respectively. CONCLUSION: Biomarkers of pericellular fibrosis decrease in early-stage NAFLD after patients undergo bariatric surgery and potentially reflect an improvement in liver histology.

Single-cell transcriptome and cell type-specific molecular pathways of human non-alcoholic steatohepatitis.

The aim of this study is to characterize cell type-specific transcriptional signatures in non-alcoholic steatohepatitis (NASH) to improve our understanding of the disease. We performed single-cell RNA sequencing on liver biopsies from 10 patients with NASH. We applied weighted gene co-expression network analysis and validated our findings using a publicly available RNA sequencing data set derived from 160 patients with non-alcoholic fatty liver disease (NAFLD) and 24 controls with normal liver histology. Our study provides a comprehensive single-cell analysis of NASH pathology in humans, describing 19,627 single-cell transcriptomes from biopsy-proven NASH patients. Our data suggest that the previous notion of "NASH-associated macrophages" can be explained by an up-regulation of normally existing subpopulations of liver macrophages. Similarly, we describe two distinct populations of activated hepatic stellate cells, associated with the level of fibrosis. Finally, we find that the expression of several circulating markers of NAFLD are co-regulated in hepatocytes together with predicted effector genes from NAFLD genome-wide association studies (GWAS), coupled to abnormalities in the complement system. In sum, our single-cell transcriptomic data set provides insights into novel cell type-specific and general biological processes associated with inflammation and fibrosis, emphasizing the importance of studying cell type-specific biological processes in human NASH.

Cardiovascular Mapping in Cirrhosis From the Compensated Stage to Hepatorenal Syndrome: A Magnetic Resonance Study.

INTRODUCTION: Arterial vasodilation and hyperdynamic circulation are considered hallmarks of the pathophysiological mechanisms of decompensation in cirrhosis. However, detailed characterization of peripheral, splanchnic, renal, and cardiac hemodynamic have not previously been published in a spectrum from healthy stage to advanced decompensated liver disease with hepatorenal syndrome-acute kidney injury (HRS-AKI). METHODS: We included 87 patients with cirrhosis and 27 healthy controls in this prospective cohort study. The population comprised patients with compensated cirrhosis (n = 27) and decompensated cirrhosis (n = 60); patients with decompensated cirrhosis were further separated into subsets of responsive ascites (33), refractory ascites (n = 16), and HRS-AKI (n = 11). We measured portal pressure and assessed regional blood flow by magnetic resonance imaging. RESULTS: Patients with compensated cirrhosis experienced higher azygos venous flow and higher hepatic artery flow fraction of cardiac index than controls ( P < 0.01), but other flow parameters were not significantly different. Patients with decompensated cirrhosis experienced significantly higher cardiac index ( P < 0.01), higher superior mesenteric artery flow ( P = 0.01), and lower systemic vascular resistance ( P < 0.001) compared with patients with compensated cirrhosis. Patients with HRS-AKI had the highest cardiac output and lowest renal flow of all groups ( P < 0.01 and P = 0.02, respectively). Associations of single hemodynamic parameters were stronger with model for end-stage liver disease than with portal pressure. DISCUSSION: The regional cardiocirculatory changes seem closely linked to clinical symptoms with 3 distinguished hemodynamic stages from compensated to decompensated cirrhosis and, finally, to HRS-AKI. The attenuated renal perfusion despite high cardiac output in patients with HRS-AKI challenges the prevailing pathophysiological hypothesis of cardiac dysfunction as a causal factor in HRS-AKI. Finally, magnetic resonance imaging seems an accurate and reliable noninvasive method to assess hemodynamics and has potential as a diagnostic tool in patients with cirrhosis.