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, and 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. Patients with AIH and MASLD 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.NEW & NOTEWORTHY Patients with autoimmune liver disease but without overt diabetes display glucose disturbances early on in their disease course. We identified pathophysiological traits specific to these patients including altered incretin responses.

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.

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.

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.

High Accuracy in Classifying Endoscopic Severity in Ulcerative Colitis Using Convolutional Neural Network.

INTRODUCTION: The evaluation of endoscopic disease severity is a crucial component in managing patients with ulcerative colitis (UC). However, endoscopic assessment suffers from substantial intraobserver and interobserver variations, limiting the reliability of individual assessments. Therefore, we aimed to develop a deep learning model capable of distinguishing active from healed mucosa and differentiating between different endoscopic disease severity degrees. METHODS: One thousand four hundred eighty-four unique endoscopic images from 467 patients were extracted for classification. Two experts classified all images independently of one another according to the Mayo endoscopic subscore (MES). In cases of disagreement, a third expert classified the images. Different convolutional neural networks were considered for automatically classifying UC severity. Five-fold cross-validation was used to develop and select the final model. Afterward, unseen test data sets were used for model evaluation. RESULTS: In the most challenging task-distinguishing between all categories of MES-our final model achieved a test accuracy of 0.84. When evaluating this model on the binary tasks of distinguishing MES 0 vs 1-3 and 0-1 vs 2-3, it achieved accuracies of 0.94 and 0.93 and areas under the receiver operating characteristic curves of 0.997 and 0.998, respectively. DISCUSSION: We have developed a highly accurate, new, automated way of evaluating endoscopic images from patients with UC. We have demonstrated how our deep learning model is capable of distinguishing between all 4 MES levels of activity. This new automated approach may optimize and standardize the evaluation of disease severity measured by the MES across centers no matter the level of medical expertise.

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.

Determination of hepatic clearance by derivations of the indocyanine green retention test in cirrhosis.

BACKGROUND AND AIM: The study was undertaken in order to compare single injection indocyanine green (ICG)-clearances with the steady-state ICG-clearance (ICGCl ) in patients with cirrhosis in order to assess the most accurate estimate for ICG-clearance and to relate the ICG-clearances to established indicators of liver dysfunction. METHODS: Thirty-eight patients (male 29) with cirrhosis (Child-Turcotte class A 8, class B 21, and class C 9) were studied during a hemodynamic investigation. A single injection of ICG was followed by blood samples for 5, 10, 15, and 20 min. The dose/plasma area clearance (ClA ) and plasma volume · initial slope clearance (ClPV ) were determined and compared with the steady-state infusion/plasma concentration ratio clearance (ICGCl ). RESULTS: The ClA (310; 214; 502 mL/min) and ClPV (294; 164; 481 mL/min) correlated closely with ICGCl (243; 120; 383 mL/min [median; interquartile range], R = 0.95-0.98, P < 0.000), but were significantly higher than ICGCl (P < 0.001). All three clearance measures correlated significantly with biochemical and hemodynamic variables of liver dysfunction (P < 0.05-0.000). All three ICG-clearances showed significantly lower values in patients with ascites compared to those without, and lower ICG-clearance values were present in patients with esophageal varices compared to those without (P < 0.05-0.002). CONCLUSION: Single injection markers (ClA and ClPV ) of the steady-state ICG-clearance as derived from the ICG-retention curve and the plasma volume correlate with ICGCl and established variables of portal hypertension and liver cell bile excretory dysfunction. Therefore, these markers can safely replace the more costly ICGCl .

Increased Prevalence of Liver Fibrosis in People Living With Human Immunodeficiency Virus Without Viral Hepatitis Compared to Population Controls.

BACKGROUND: Liver fibrosis is associated with poor liver-related outcomes and mortality. People with human immunodeficiency virus (PWH) may be at increased risk. We aimed to estimate the prevalence and factors associated with liver fibrosis in PWH compared to population controls. METHODS: This was a cross-sectional cohort study comparing 342 PWH with 2190 population controls aged 50-70 years.Transient elastography was performed and elevated liver stiffness measurement (LSM) defined as 7.6 kPa as a proxy for significant liver fibrosis. Adjusted odds ratios (aORs) and 95% confidence intervals (95% CIs) were computed by logistic regression. RESULTS: The prevalence of elevated LSM was higher in PWH than in uninfected controls (12% vs 7%; P < .01). Human immunodeficiency virus (HIV) infection was independently associated with elevated LSM. In multivariate analysis, elevated LSM was associated with HIV (aOR, 1.84 [95% CI, 1.17-2.88]; P < .01); higher age (per decade: aOR, 3.34 [95% CI, 1.81-6.18]; P < .01); alanine aminotransferase (ALT) (per 10 IU/L: aOR, 1.25 [95% CI, 1.05-1.49]; P < .01); body mass index (BMI) (per 1 kg/m2: aOR, 1.17 [95% CI, 1.05-1.29]; P < .01), and previous exposure to didanosine (per year: aOR, 2.26 [95% CI, 1.01-5.06]; P = .04). CONCLUSIONS: The prevalence of elevated LSM was higher in PWH compared to population controls. Higher age, BMI, ALT, previous exposure to didanosine, and positive HIV status were independently associated with higher odds of elevated LSM.

Differential inflammasome activation predisposes to acute-on-chronic liver failure in human and experimental cirrhosis with and without previous decompensation.

OBJECTIVE: Systemic inflammation predisposes acutely decompensated (AD) cirrhosis to the development of acute-on-chronic liver failure (ACLF). Supportive treatment can improve AD patients, becoming recompensated. Little is known about the outcome of patients recompensated after AD. We hypothesise that different inflammasome activation is involved in ACLF development in compensated and recompensated patients. DESIGN: 249 patients with cirrhosis, divided into compensated and recompensated (previous AD), were followed prospectively for fatal ACLF development. Two external cohorts (n=327) (recompensation, AD and ACLF) were included. Inflammasome-driving interleukins (ILs), IL-1α (caspase-4/11-dependent) and IL-1ß (caspase-1-dependent), were measured. In rats, bile duct ligation-induced cirrhosis and lipopolysaccharide exposition were used to induce AD and subsequent recompensation. IL-1α and IL-1ß levels and upstream/downstream gene expression were measured. RESULTS: Patients developing ACLF showed higher baseline levels of ILs. Recompensated patients and patients with detectable ILs had higher rates of ACLF development than compensated patients. Baseline CLIF-C (European Foundation for the study of chronic liver failure consortium) AD, albumin and IL-1α were independent predictors of ACLF development in compensated and CLIF-C AD and IL-1ß in recompensated patients. Compensated rats showed higher IL-1α gene expression and recompensated rats higher IL-1ß levels with higher hepatic gene expression. Higher IL-1ß detection rates in recompensated patients developing ACLF and higher IL-1α and IL-1ß detection rates in patients with ACLF were confirmed in the two external cohorts. CONCLUSION: Previous AD is an important risk factor for fatal ACLF development and possibly linked with inflammasome activation. Animal models confirmed the results showing a link between ACLF development and IL-1α in compensated cirrhosis and IL-1ß in recompensated cirrhosis.

Hepatic Steatosis Associated With Exposure to Elvitegravir and Raltegravir.

Moderate-to-severe hepatic steatosis in people living with human immunodeficiency virus (HIV) without viral hepatitis or excessive alcohol intake was associated with cumulative exposure to stavudine, elvitegravir, and raltegravir. Prospective trials are required to establish a causal association. Clinical Trials Registration. NCT02382822.

Coronavirus disease 2019, immune-mediated inflammatory diseases and immunosuppressive therapies - A Danish population-based cohort study.

BACKGROUND: Limited data exist regarding the disease course of coronavirus disease 2019 (COVID-19) and its relationship with immunosuppressants among patients with immune-mediated inflammatory diseases (IMIDs). Therefore, this study aims to investigate the association between COVID-19, frequent rheumatological, dermatological, gastrointestinal, and neurological IMIDs and immunosuppressants. METHODS: We conducted a Danish population-based cohort study including all residents living within Capital Region of Denmark and Region Zealand from January 28th, 2020 until September 15th, 2020 with the only eligibility criterion being a test for SARS-CoV-2 via reverse transcription-polymerase chain-reaction. Main outcomes included development of COVID-19, COVID-19-related hospitalization and mortality. RESULTS: COVID-19 was less common among patients with IMIDs than the background population (n = 328/20,513 (1.60%) and n = 10,792/583,788(1.85%), p < 0.01, respectively). However, those with IMIDs had a significantly higher risk of COVID-19-related hospitalization (31.1% and 18.6%, p < 0.01, respectively) and mortality (9.8% and 4.3%, p < 0.01, respectively), which were associated with patients older than 65 years, and presence of comorbidities. Furthermore, systemic steroids were independently associated with a severe course of COVID-19 (Odds ratio (OR) = 3.56 (95%CI 1.83-7.10), p < 0.01), while biologic therapies were associated with a reduced risk hereof (OR = 0.47 (95%CI 0.22-0.95), p = 0.04). Patients suspending immunosuppressants due to COVID-19 had an increased risk of subsequent hospitalization (OR = 3.59 (95%CI 1.31-10.78), p = 0.02). CONCLUSION: This study found a lower occurrence, but a more severe disease course, of COVID-19 among patients with IMIDs, which was associated with the use of systemic steroids for IMIDs and suspension of other immunosuppressants. This study emphasizes the importance of weighing risks before suspending immunosuppressants during COVID-19.

Using MR elastography to assess portal hypertension and response to beta-blockers in patients with cirrhosis.

BACKGROUND: MR elastography can determine organ-related stiffness, which reflects the degree of fibrosis. Liver stiffness increases in cirrhosis, and stiffness increases further post-prandially due to increased portal blood in-flow. Non-selective beta-blockers (NSBB) reduce the portal venous inflow, but their effect on liver and spleen stiffness are disputed. AIMS: To assess whether MR elastography of the liver or spleen reflects the severity of cirrhosis, whether treatment with NSBB changes liver and spleen stiffness and whether changes in stiffness can predict the effect of NSBB on portal pressure. METHODS: Fifty-two patients with cirrhosis underwent liver vein catheterization and two-dimensional (2D) MR elastography on separate days. Thirty-six of the patients had a hepatic venous pressure gradient (HVPG) of ≥12 mmHg and were tested prior to, and after, intravenous infusion of NSBB using HVPG measurement and MR elastography. RESULTS: HVPG showed a strong, positive, linear relationship with liver stiffness (r2  = 0.92; P < .001) and spleen stiffness (r2  = 0.94; P < .001). The cut-off points for identifying patients with a HVPG ≥ 12 mmHg were 7.7 kPa for liver stiffness (sensitivity 0.78, specificity 0.64) and 10.5 kPa for spleen stiffness (sensitivity 0.8, specificity 0.79). Intravenous administration of NSBB significantly decreased spleen stiffness by 6.9% (CI: 3.5-10.4, P < .001), but NSBB had no consistent effect on liver stiffness. However, changes in spleen stiffness were not related to the HVPG response (P = .75). CONCLUSIONS: Two-dimensional MR elastographic estimation of liver or spleen stiffness reflects the degree of portal hypertension in patients with liver cirrhosis, but changes in stiffness after NSBB do not predict the effect on HVPG.

A Danish population-based case series of patients with liver cirrhosis and coronavirus disease 2019.

OBJECTIVES: Coronavirus disease 2019 (COVID-19) is an ongoing major health emergency, but its occurrence and clinical impact on patients withliver cirrhosis is unknown. Therefore, we conducted a population-based study of 2.6 million Danish citizens investigating the occurrence and impact of COVID-19 in patients with liver cirrhosis. MATERIALS AND METHODS: A prospective population-based cohort study was conducted in the Capital Region of Denmark and Region Zealand in the study period between 1 March 2020 up until 31 May 2020, with the only eligibility criteria being a reverse-transcriptase polymerase chain reaction for presence of viral genomic material confirming COVID-19. The patients were subsequently stratified according to presence of pre-existing liver cirrhosis. RESULTS: Among 575,935 individuals tested, 1713 patients had a diagnosis of cirrhosis. COVID-19 occurredsignificantly lessamongpatients with cirrhosis (n = 15; 0.9%, p < .01) compared with the population without cirrhosis (n = 10,593; 1.8%). However, a large proportion (n = 6;40.0%) required a COVID-19 related hospitalization which was correlated with higher values of alanine aminotransferase (p < .01) and lactate dehydrogenase (p = .04). In addition, one-in-three (n = 2; 13.3%) required intensive therapy. Four patients died (26.7%) and mortality was associated with higher MELD scores, co-existing type 2 diabetes, and bacterial superinfections. CONCLUSION: In conclusion, patientswith cirrhosis may have a lower risk of COVID-19; but a higher risk of complications hereto and mortality.

Fecal microbiota transplantation in hepatic encephalopathy: a systematic review.

Hepatic encephalopathy (HE) is a reversible neurocognitive dysfunction that ranges in severity from subclinical alterations to coma. Patients with chronic liver disease are predisposed to HE due to metabolic failure and portosystemic shunting of toxins, of which ammonia is believed to be the main toxic chemical. Fecal microbiota transplantation (FMT) may reduce ammonia synthesis by altering the gut microbiota composition to a taxon low in urease, diminish uptake of ammonia by reestablishing the integrity of the intestinal barrier and increase ammonia clearance by improving liver function. In this systematic review, we summarize the insights of the current literature examining FMT as a treatment for HE.PubMed and EMBASE were searched on 08 February 2021 using the MeSH terms 'fecal microbiota transplantation & hepatic encephalopathy' and the abbreviations 'FMT & HE'.Eight studies fulfilled our inclusion criteria, comprising two randomized clinical trials, three case reports and three rodent studies. Thirty-nine patients with HE were treated with FMT. Thirty-nine rodents received FMT in laboratory tests. FMT improved neurocognitive test results in four human studies and two rodent studies. Microbiota originating from donors was found in human recipients one year post-FMT. Readmission of patients was lower after treatment with FMT compared to standard of care.FMT may improve neurocognitive function and reduce serious adverse events in patients with HE, but the studies conducted so far have been small and their long-term follow-up is limited. Large-scale, randomized and controlled trials are needed to validate and help standardize the clinical application of FMT in cases of HE.

Vedolizumab as first-line biological therapy in elderly patients and those with contraindications for anti-TNF therapy: a real-world, nationwide cohort of patients with inflammatory bowel diseases.

BACKGROUND: Data from real-life populations about vedolizumab as first-line biological therapy for ulcerative colitis (UC) and Crohn's disease (CD) are emerging. OBJECTIVE: To investigate the efficacy and safety of vedolizumab in bio-naïve patients with UC and CD. METHODS: A Danish nationwide cohort study was conducted between November 2014 and November 2019. Primary outcomes were clinical remission, steroid-free clinical remission, and sustained clinical remission from weeks 14 through 52. RESULTS: The study included 56 patients (UC:31, CD:25) who initiated treatment with vedolizumab mainly because of contraindications to anti-TNFs, of whom 54.8 and 24.0%, respectively received systemic steroids at the initiation. Rates of clinical remission at weeks 6, 14, and 52 were 32.0, 48.0, and 40.0%, respectively, in UC, and 36.8, 36.8, and 47.4% in CD. Steroid-free clinical remission at week 52 was achieved among 36.0 and 47.4% of UC and CD patients, while sustained clinical remission was achieved in 32.0 and 36.8%. Lack of remission was associated with being female (68.8 vs. 11.1%, p = .01) in UC and non-structuring, non-penetrating behavior in CD (90.0 vs. 44.4%, p = .03); however, this was not confirmed in multivariate analysis. Discontinuation due to primary non-response occurred in 20.0 and 5.3% of UC and CD patients, respectively, while rates of secondary loss of response were 12.0 and 5.3% after 52 weeks of follow-up. Vedolizumab was well-tolerated as only one UC patient experienced a serious adverse event. CONCLUSION: Vedolizumab is effective in the achievement of short-term, long-term, and steroid-free clinical remission in bio-naïve UC and CD patients.

Prevalence and Risk Factors of Moderate-to-Severe Hepatic Steatosis in Human Immunodeficiency Virus Infection: The Copenhagen Co-morbidity Liver Study.

BACKGROUND: People with human immunodeficiency virus (PWH) may be at risk of nonalcoholic fatty liver disease. We compared the prevalence of moderate-to-severe hepatic steatosis (M-HS) in PWH with human immunodeficiency virus (HIV)-uninfected controls and determined risk factors for M-HS in PWH. METHODS: The Copenhagen Co-Morbidity in HIV Infection study included 453 participants, and the Copenhagen General Population Study included 765 participants. None had prior or current viral hepatitis or excessive alcohol intake. Moderate-to-severe hepatic steatosis was assessed by unenhanced computed tomography liver scan defined by liver attenuation ≤48 Hounsfield units. Adjusted odds ratios (aORs) were computed by adjusted logistic regression. RESULTS: The prevalence of M-HS was lower in PWH compared with uninfected controls (8.6% vs 14.2%, P < .01). In multivariable analyses, HIV (aOR, 0.44; P < .01), female sex (aOR, 0.08; P = .03), physical activity level (aOR, 0.09; very active vs inactive; P < .01), and alcohol (aOR, 0.89 per unit/week; P = .02) were protective factors, whereas body mass index (BMI) (aOR, 1.58 per 1 kg/m2; P < .01), alanine transaminase (ALT) (aOR, 1.76 per 10 U/L; P < .01), and exposure to integrase inhibitors (aOR, 1.28 per year; P = .02) were associated with higher odds of M-HS. CONCLUSIONS: Moderate-to-severe hepatic steatosis is less common in PWH compared with demographically comparable uninfected controls. Besides BMI and ALT, integrase inhibitor exposure was associated with higher prevalence of steatosis in PWH.

The PREDICT study uncovers three clinical courses of acutely decompensated cirrhosis that have distinct pathophysiology.

BACKGROUND & AIMS: Acute decompensation (AD) of cirrhosis is defined as the acute development of ascites, gastrointestinal hemorrhage, hepatic encephalopathy, infection or any combination thereof, requiring hospitalization. The presence of organ failure(s) in patients with AD defines acute-on-chronic liver failure (ACLF). The PREDICT study is a European, prospective, observational study, designed to characterize the clinical course of AD and to identify predictors of ACLF. METHODS: A total of 1,071 patients with AD were enrolled. We collected detailed pre-specified information on the 3-month period prior to enrollment, and clinical and laboratory data at enrollment. Patients were then closely followed up for 3 months. Outcomes (liver transplantation and death) at 1 year were also recorded. RESULTS: Three groups of patients were identified. Pre-ACLF patients (n = 218) developed ACLF and had 3-month and 1-year mortality rates of 53.7% and 67.4%, respectively. Unstable decompensated cirrhosis (UDC) patients (n = 233) required ≥1 readmission but did not develop ACLF and had mortality rates of 21.0% and 35.6%, respectively. Stable decompensated cirrhosis (SDC) patients (n = 620) were not readmitted, did not develop ACLF and had a 1-year mortality rate of only 9.5%. The 3 groups differed significantly regarding the grade and course of systemic inflammation (high-grade at enrollment with aggravation during follow-up in pre-ACLF; low-grade at enrollment with subsequent steady-course in UDC; and low-grade at enrollment with subsequent improvement in SDC) and the prevalence of surrogates of severe portal hypertension throughout the study (high in UDC vs. low in pre-ACLF and SDC). CONCLUSIONS: Acute decompensation without ACLF is a heterogeneous condition with 3 different clinical courses and 2 major pathophysiological mechanisms: systemic inflammation and portal hypertension. Predicting the development of ACLF remains a major future challenge. CLINICALTRIALS. GOV NUMBER: NCT03056612. LAY SUMMARY: Herein, we describe, for the first time, 3 different clinical courses of acute decompensation (AD) of cirrhosis after hospital admission. The first clinical course includes patients who develop acute-on-chronic liver failure (ACLF) and have a high short-term risk of death - termed pre-ACLF. The second clinical course (unstable decompensated cirrhosis) includes patients requiring frequent hospitalizations unrelated to ACLF and is associated with a lower mortality risk than pre-ACLF. Finally, the third clinical course (stable decompensated cirrhosis), includes two-thirds of all patients admitted to hospital with AD - patients in this group rarely require hospital admission and have a much lower 1-year mortality risk.

Dobutamine reverses the cardio-suppressive effects of terlipressin without improving renal function in cirrhosis and ascites: a randomized controlled trial.

Acute kidney injury and hepatorenal syndrome (HRS) are frequent complications in patients with cirrhosis and ascites. First-line treatment is terlipressin, which reverses HRS in ~40% of patients but also lowers cardiac output (CO). We aimed to investigate whether reversing the cardio-suppressive effect of terlipressin with the ß-adrenoceptor agonist dobutamine would increase CO and thereby increase the glomerular filtration rate (GFR). We randomized 25 patients with cirrhosis, ascites, and impaired renal function (2:2:1): group A received terlipressin followed by the addition of dobutamine; group B received dobutamine and terlipressin as monotherapies; and group C received placebo. Renal and cardiac functions were assessed during 8 clearance periods of 30 min, and concentrations of vasoactive hormones were measured. Dobutamine as a monotherapy increased CO (1.03 L/min, P < 0.01) but had no significant effects on GFR. Renin (P < 0.05), angiotensin II (P < 0.005), and aldosterone (P < 0.05) increased after dobutamine infusion. Terlipressin as a monotherapy improved GFR (18.9 mL·min-1·m-2, P = 0.005) and mean arterial pressure (MAP) (14 mmHg, P = 0.001) but reduced CO (-0.92 L/min, P < 0.005) and renin (P < .005). A combined treatment of dobutamine and terlipressin had a positive effect on CO (1.19 L/min, P < 0.05) and increased renin (P < 0.005), angiotensin II (P < 0.005), and aldosterone (P < 0.05), but it had no significant effects on MAP or GFR. Dobutamine reversed the cardio-suppressive effect of terlipressin in cirrhosis, ascites, and impaired renal function. However, dobutamine reduced peripheral vascular resistance, activated renin-angiotensin-aldosterone system, and did not improve GFR compared with terlipressin as a monotherapy. Therefore, dobutamine cannot be recommended in cirrhosis and ascites.NEW & NOTEWORTHY This study shows that the cardio-suppressive effects of the vasopressin receptor agonist terlipressin can be reversed by dobutamine. This is a novel observation in patients with decompensated cirrhosis. Furthermore, we show that dobutamine reduced the peripheral vascular resistance and activated the renin-angiotensin system, whereas renal function was not further improved by terlipressin alone.

Poor Concordance Between Liver Stiffness and Noninvasive Fibrosis Scores in HIV Infection Without Viral Hepatitis.

People living with human immunodeficiency virus (PLWH) are at higher risk of liver fibrosis compared with the general population. As liver fibrosis is independently associated with poor long-term liver related outcomes and mortality,1 early detection is extremely important. Liver biopsy is considered gold standard for the diagnosis of liver fibrosis. However, this invasive procedure is only suitable for a selected group of patients because of the risk of serious complications. We aimed to estimate the concordance between vibration-controlled transient elastography (VCTE) and simple noninvasive liver fibrosis scores-Fibrosis-4 index (FIB4), aspartate aminotransferase-to-platelet ratio index (APRI), and nonalcoholic fatty liver disease fibrosis score (NFS)-in PLWH without viral hepatitis.

Cardiodynamic state is associated with systemic inflammation and fatal acute-on-chronic liver failure.

BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF) is characterized by high short-term mortality and systemic inflammation (SI). Recently, different cardiodynamic states were shown to independently predict outcomes in cirrhosis. The relationship between cardiodynamic states, SI, and portal hypertension and their impact on ACLF development remains unclear. The aim of this study was therefore to evaluate the interplay of cardiodynamic state and SI on fatal ACLF development in cirrhosis. RESULTS: At inclusion, hemodynamic measures including cardiac index (CI) and hepatic venous pressure gradient of 208 patients were measured. Patients were followed prospectively for fatal ACLF development (primary endpoint). SI was assessed by proinflammatory markers such as interleukins (ILs) 6 and 8 and soluble IL-33 receptor (sIL-33R). Patients were divided according to CI (<3.2; 3.2-4.2; >4.2 L/min/m2 ) in hypo- (n = 84), normo- (n = 69) and hyperdynamic group (n = 55). After a median follow-up of 3 years, the highest risk of fatal ACLF was seen in hyperdynamic (35%) and hypodynamic patients (25%) compared with normodynamic (14%) (P = .011). Hyperdynamic patients showed the highest rate of SI. The detectable level of IL-6 was an independent predictor of fatal ACLF development. CONCLUSIONS: Cirrhotic patients with hyperdynamic and hypodynamic circulation have a higher risk of fatal ACLF. Therefore, the cardiodynamic state is strongly associated with SI, which is an independent predictor of development of fatal ACLF.