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.

Portosystemic Hepatic Encephalopathy Scores (PHES) differ between Danish and German healthy populations despite their geographical and cultural similarities.

Minimal hepatic encephalopathy (MHE) is common in liver cirrhosis and is identified by psychometric tests. The portosystemic hepatic encephalopathy score (PHES) is the most widely used and serves as an inter-study comparator. PHES has not been standardised for use in the Danish population, where German normal values have been applied until now based on the notion that the populations are comparable. This study aimed to evaluate if German PHES normal values can be applied in the Danish population and establish Danish normal values if needed. 200 Danish and 217 German healthy persons underwent Number Connection Test A and B (NCT), Line Tracing Test (LTT), Digit Symbol Test (DST), and Serial Dotting Test (SDT), and based on performance, PHES was calculated. German and Danish PHES performance declined with age in all subtests but more rapidly in Danes. Both German and Danish norms were impacted by gender and education, but to a different extent in the single tests of the test battery. Accordingly, there was a need for specific Danish normal values, which are presented here. Applying the new Danish normal values instead of the German in patients with cirrhosis yielded a lower percentage of out-of-norm performances (58% vs. 66%) and, hence, a lower prevalence of MHE. Danes and Germans perform differently on PHES, and therefore, normal German values cannot be used in Danish patients. Danish normal values are presented here and yield a lower number of 'out of norm' performances.

Umbilical Hernia Repair in Patients with Cirrhosis and in Patients with Severe Comorbidities-A Nationwide Cohort Study.

INTRODUCTION: Umbilical hernia is a frequent condition in patients with cirrhosis. The aim of the study was to evaluate the risks associated with umbilical hernia repair in patients with cirrhosis in the elective and emergency setting. Secondly, to compare patients with cirrhosis with a population of patients with equally severe comorbidities but without cirrhosis. METHODS: Patients with cirrhosis who underwent umbilical hernia repair from January 1, 2007, to December 31, 2018, were included from the Danish Hernia Database. A control group of patients with a similar Charlson score (≥ 3) without cirrhosis was generated using propensity score matching. The primary outcome was postoperative re-intervention within 30 days following hernia repair. Secondary outcomes were mortality within 90 days and readmission within 30 days following hernia repair. RESULTS: A total of 252 patients with cirrhosis and 504 controls were included. Emergency repair in patients with cirrhosis was associated with a significantly increased rate of re-intervention (54/108 (50%) vs. 24/144 (16.7%), P < 0.001), 30-day readmission rate (50/108 (46.3%) compared with elective repair vs. 36/144 (25%) (P < 0.0001)), and 90-day mortality (18/108 (16.7%) vs. 5/144 (3.5%), P < 0.001). Patients with cirrhosis were more likely to undergo a postoperative re-intervention compared with comorbid patients without cirrhosis (OR = 2.10; 95% CI [1.45-3.03]). CONCLUSION: Patients with cirrhosis and other severe comorbidity undergo emergency umbilical hernia repair frequently. Emergency repair is associated with increased risk of poor outcome. Patients with cirrhosis undergo a postoperative reintervention more frequently than patients with other severe comorbidity undergoing umbilical hernia repair.

Rifaximin for prevention and treatment of hepatic encephalopathy in people with cirrhosis.

BACKGROUND: Hepatic encephalopathy describes the spectrum of neuropsychiatric changes that may complicate the course of cirrhosis and detrimentally affect outcomes. Ammonia plays a key role in its development. Rifaximin is a non-absorbable antibiotic that inhibits urease-producing bacteria and reduces absorption of dietary and bacterial ammonia. OBJECTIVES: To evaluate the beneficial and harmful effects of rifaximin versus placebo, no intervention, or non-absorbable disaccharides for: (i) the prevention of hepatic encephalopathy, and (ii) the treatment of minimal and overt hepatic encephalopathy, in people with cirrhosis, both when used alone and when combined with a non-absorbable disaccharide. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group Clinical Trials Register, CENTRAL, MEDLINE, Embase, three other databases, the reference lists of identified papers, and relevant conference proceedings. We wrote to authors and pharmaceutical companies for information on other published, unpublished, or ongoing trials. Searches were performed to January 2023. SELECTION CRITERIA: We included randomised clinical trials assessing prevention or treatment of hepatic encephalopathy with rifaximin alone, or with a non-absorbable disaccharide, versus placebo/no intervention, or a non-absorbable disaccharide alone. DATA COLLECTION AND ANALYSIS: Six authors independently searched for studies, extracted data, and validated findings. We assessed the design, bias risk, and participant/intervention characteristics of the included studies. We assessed mortality, serious adverse events, health-related quality of life, hepatic encephalopathy, non-serious adverse events, blood ammonia, Number Connection Test-A, and length of hospital stay. MAIN RESULTS: We included 41 trials involving 4545 people with, or at risk for, developing hepatic encephalopathy. We excluded 89 trials and identified 13 ongoing studies. Some trials involved participants with more than one type of hepatic encephalopathy or more than one treatment comparison. Hepatic encephalopathy was classed as acute (13 trials), chronic (7 trials), or minimal (8 trials), or else participants were considered at risk for its development (13 trials). The control groups received placebo (12 trials), no/standard treatment (1 trial), or a non-absorbable disaccharide (14 trials). Eighteen trials assessed rifaximin plus a non-absorbable disaccharide versus a non-absorbable disaccharide alone. We classified 11 trials as at high risk of overall bias for mortality and 28 for non-mortality outcomes, mainly due to lack of blinding, incomplete outcome data, and selective reporting. Compared to placebo/no intervention, rifaximin likely has no overall effect on mortality (risk ratio (RR) 0.83, 95% confidence interval (CI) 0.50 to 1.38; P = 48, I2 = 0%; 13 trials, 1007 participants; moderate-certainty evidence), and there may be no overall effect when compared to non-absorbable disaccharides (RR 0.99, 95% CI 0.49 to 1.97; P = 0.97, I2 = 0%; 10 trials, 786 participants; low-certainty evidence). However, there is likely a reduction in the overall risk of mortality when comparing rifaximin plus a non-absorbable disaccharide to a non-absorbable disaccharide alone (RR 0.69, 95% CI 0.55 to 0.86; number needed to treat for an additional beneficial outcome (NNTB) = 22; P = 0.001, I2 = 0%; 14 trials, 1946 participants; moderate-certainty evidence). There is likely no effect on the overall risk of serious adverse events when comparing rifaximin to placebo/no intervention (RR 1.05, 95% CI 0.83 to 1.32; P = 68, I2 = 0%; 9 trials, 801 participants; moderate-certainty evidence) and there may be no overall effect when compared to non-absorbable disaccharides (RR 0.97, 95% CI 0.66 to 1.40; P = 85, I2 = 0%; 8 trials, 681 participants; low-certainty evidence). However, there was very low-certainty evidence that use of rifaximin plus a non-absorbable disaccharide may be associated with a lower risk of serious adverse events than use of a non-absorbable disaccharide alone (RR 0.66, 95% CI 0.45 to 0.98; P = 0.04, I2 = 60%; 7 trials, 1076 participants). Rifaximin likely results in an overall effect on health-related quality of life when compared to placebo/no intervention (mean difference (MD) -1.43, 95% CI -2.87 to 0.02; P = 0.05, I2 = 81%; 4 trials, 214 participants; moderate-certainty evidence), and may benefit health-related quality of life in people with minimal hepatic encephalopathy (MD -2.07, 95% CI -2.79 to -1.35; P < 0.001, I2 = 0%; 3 trials, 176 participants). The overall effect on health-related quality of life when comparing rifaximin to non-absorbable disaccharides is very uncertain (MD -0.33, 95% CI -1.65 to 0.98; P = 0.62, I2 = 0%; 2 trials, 249 participants; very low-certainty evidence). None of the combined rifaximin/non-absorbable disaccharide trials reported on this outcome. There is likely an overall beneficial effect on hepatic encephalopathy when comparing rifaximin to placebo/no intervention (RR 0.56, 95% CI 0.42 to 0.77; NNTB = 5; P < 0.001, I2 = 68%; 13 trials, 1009 participants; moderate-certainty evidence). This effect may be more marked in people with minimal hepatic encephalopathy (RR 0.40, 95% CI 0.31 to 0.52; NNTB = 3; P < 0.001, I2 = 10%; 6 trials, 364 participants) and in prevention trials (RR 0.71, 95% CI 0.56 to 0.91; NNTB = 10; P = 0.007, I2 = 36%; 4 trials, 474 participants). There may be little overall effect on hepatic encephalopathy when comparing rifaximin to non-absorbable disaccharides (RR 0.85, 95% CI 0.69 to 1.05; P = 0.13, I2 = 0%; 13 trials, 921 participants; low-certainty evidence). However, there may be an overall beneficial effect on hepatic encephalopathy when comparing rifaximin plus a non-absorbable disaccharide to a non-absorbable disaccharide alone (RR 0.58, 95% CI 0.48 to 0.71; NNTB = 5; P < 0.001, I2 = 62%; 17 trials, 2332 participants; low-certainty evidence). AUTHORS' CONCLUSIONS: Compared to placebo/no intervention, rifaximin likely improves health-related quality of life in people with minimal hepatic encephalopathy, and may improve hepatic encephalopathy, particularly in populations with minimal hepatic encephalopathy and when it is used for prevention. Rifaximin likely has no overall effect on mortality, serious adverse events, health-related quality of life, or hepatic encephalopathy compared to non-absorbable disaccharides. However, when used in combination with a non-absorbable disaccharide, it likely reduces overall mortality risk, the risk of serious adverse events, improves hepatic encephalopathy, reduces the length of hospital stay, and prevents the occurrence/recurrence of hepatic encephalopathy. The certainty of evidence for these outcomes is very low to moderate; further high-quality trials are needed.

Indications and methods for measuring portal hypertension in cirrhosis.

Background and objectives: Over the last decade our understanding of the pathophysiology of portal hypertension has increased. Novel diagnostic technologies have facilitated and improved the diagnosis and treatment of hepatic fibrosis and cirrhosis. With this review we aim to provide an overview of contemporary diagnostic principles of portal hypertension and indications for measuring portal pressure in cirrhosis.Methods: By review of current literature, we assessed new and old principles of measuring portal hypertension and the diagnostic values of the methods.Results: Invasive measurement of the portal pressure is still the gold standard to quantitate portal hypertension and to assess response to vasoactive treatment. The size of the portal pressure is important to assess since it contains information on the course of the disease and risk of developing hepatic decompensation, hepatocellular carcinoma, and mortality. Reliable non-invasive Elastography techniques are emerging that adequately assess portal pressure, but the available methods are not yet sufficiently accurate.Conclusion: Although elastography techniques provide valuable information and are good monitoring tools, liver vein catheterization remains valuable in diagnosing and monitoring portal hypertension, especially in combination with a trans-jugular liver biopsy.

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.

Nonalcoholic Fatty Liver Disease and Cardiovascular Disease: Overlapping Mechanisms.

Nonalcoholic fatty liver disease (NAFLD) denotes a condition with excess fat in the liver. The prevalence of NAFLD is increasing, averaging > 25% of the Western population. In 25% of the patients, NAFLD progresses to its more severe form: nonalcoholic steatohepatitis and >25% of these progress to cirrhosis following activation of inflammatory and fibrotic processes. NAFLD is associated with obesity, type 2 diabetes, and the metabolic syndrome and represents a considerable and increasing health burden. In the near future, NAFLD cirrhosis is expected to be the most common cause for liver transplantation. NAFLD patients have an increased risk of developing cardiovascular disease as well as liver-related morbidity. In addition, hepatic steatosis itself appears to represent an independent cardiovascular risk factor. In the present review, we provide an overview of the overlapping mechanisms and prevalence of NAFLD and cardiovascular disease.

Arm lean mass determined by dual-energy X-ray absorptiometry is superior to characterize skeletal muscle and predict sarcopenia-related mortality in cirrhosis.

Sarcopenia worsens survival in patients with advanced liver disease including cirrhosis. In this study, we aimed to characterize skeletal muscle status by dual-energy X-ray absorptiometry (DXA) in patients with cirrhosis and examine the association between different skeletal muscle compartments and mortality. We included 231 men and 84 women (Child A, B, and C) with cirrhosis and 315 healthy matched controls (231 men and 84 women). Body composition was assessed with DXA. Appendicular skeletal muscle index (ASMI), arms index (AI), and legs index (LI) were calculated by normalizing lean mass to height squared. Low ASMI was defined as ASMI < 7.0 kg/m2 in men and <5.5 kg/m2 in women. Biochemical and hemodynamic data were recorded for cirrhotic patients and mortality data retrieved from registers. Low ASMI was more prevalent in both men (49%) and women (43%) with cirrhosis compared with healthy men (8%) and women (5%) (P < 0.001). ASMI and LI were lowest in Child B, whereas AI decreased gradually with advancing Child class. ASMI was inversely associated with mortality in men [HR = 0.74 (0.59-0.93), P < 0.01], and this was mainly driven by AI [HR = 0.37 (0.18-0.71), P < 0.01]. AI showed closer association than ASMI or LI to both the severity of liver disease and to mortality, which may be due to increasing prevalence of leg edema with disease progression in this population. Determination of arm lean mass may add information on survival in patients with cirrhosis.NEW & NOTEWORTHY Sarcopenia increases mortality in patients with end-stage liver disease. We show that arm lean mass determined by dual-energy X-ray absorptiometry is a better marker than the traditional appendicular skeletal muscle mass when predicting sarcopenia-related mortality in patients with cirrhosis of different severity. The findings add to the dispute about the optimal method for repeated assessments of skeletal muscle status in patients with cirrhosis and may have implications for clinical decision making.

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.

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.

Pathophysiological-based treatments of complications of cirrhosis.

Detailed knowledge and understanding of the pathophysiological mechanisms and changes in hepatic and splanchnic function leading to the development of haemodynamic changes and portal hypertension in patients with cirrhosis are essential since it guides the search for targets to ameliorate liver-related abnormalities. Recent research has focused on the gut-liver axis, changes in intestinal permeability, translocation of bacterial products, and inflammation as important drivers of haemodynamic alterations and thereby targets for treatment. Additionally, treatment strategies should focus on microbiotic modulation, antiangiogenics, anti-inflammatory strategies, and modulation of bile acid metabolism. This paper aims to review contemporary pathophysiological-based treatment principles of the major complications of cirrhosis and portal hypertension and future targets for treatment.

Tunneled Peritoneal Catheter for Refractory Ascites in Cirrhosis: A Randomized Case-Series.

BACKGROUND AND OBJECTIVES: Refractory ascites markedly worsens prognosis in cirrhosis. Large volume paracentesis (LVP) is standard treatment, but complications are common. In a randomized controlled case-series, we assessed a permanent tunneled peritoneal catheter versus LVP in patients with cirrhosis and ascites. MATERIALS AND METHODS: Random allocation was computer-generated, and concealment used opaque envelopes. Patients were included from January 2017 to December 2018. Inclusion criteria were cirrhosis and recurrent ascites and expected survival of more than 3 months. RESULTS: Thirteen patients were enrolled (PleurX =6 versus LVP = 7). Seven were female, ranging in age from 51 to 80 years. No procedure-related complications occurred. Two patients died due to variceal bleeding (PleurX-group) and sepsis (LVP-group). One patient was withdrawn due to hyponatremia (PleurX-group). Two patients were withdrawn due to bacterial peritonitis and infection of unknown origin (control-group). In the PleurX-group, all patients colonized the catheter, two developed bacterial peritonitis. The most common bacterial colonization was Staph. Epidermidis (n = 4). CONCLUSIONS: In selected patients, the PleurX catheter mobilizes ascites and may be an alternative to LVP. The risk of infection should be considered in each case. The impact of colonization and risk of infections needs further investigation. The present trial does not allow for statistical conclusions.

Rifaximin has no effect on hemodynamics in decompensated cirrhosis: A randomized, double-blind, placebo-controlled trial.

Decompensated cirrhosis is characterized by disturbed systemic and splanchnic hemodynamics. Bacterial translocation from the gut is considered the key driver in this process. Intestinal decontamination with rifaximin may improve hemodynamics. This double-blind, randomized, controlled trial (clinicaltrials.gov, NCT01769040) investigates the effects of rifaximin on hemodynamics, renal function, and vasoactive hormones. We randomized 54 stable outpatients with cirrhosis and ascites to rifaximin 550 mg twice a day (n = 36) or placebo twice a day (n = 18). Forty-five patients were male, mean age 56 years (±8.4), average Child score 8.3 (±1.3), and Model for End-Stage Liver Disease score 11.7 (±3.9). Measurements of hepatic venous pressure gradient, cardiac output, and systemic vascular resistance were made at baseline and after 4 weeks. The glomerular filtration rate and plasma renin, noradrenaline, lipopolysaccharide binding protein, troponin T, and brain natriuretic peptide levels were measured. Rifaximin had no effect on hepatic venous pressure gradient, mean 16.8 ± 3.8 mm Hg at baseline versus 16.6 ± 5.3 mm Hg at follow-up, compared to the placebo, mean 16.4 ± 4 mm Hg at baseline versus 16.3 ± 4.4 mm Hg at follow-up, P = 0.94. No effect was found on cardiac output, mean 6.9 ± 1.7 L/min at baseline versus 6.9 ± 2.3 L/min at follow-up, compared to placebo, mean 6.6 ± 1.9 L/min at baseline compared to 6.5 ±2.1 L/min at follow-up, P = 0.66. No effects on the glomerular filtration rate, P = 0.14, or vasoactive hormones were found. Subgroup analyses on patients with increased lipopolysaccharide binding protein and systemic vascular resistance below the mean (1,011 dynes × s/cm5 ) revealed no effect of rifaximin. CONCLUSION: Four weeks of treatment with rifaximin did not reduce the hepatic venous pressure gradient or improve systemic hemodynamics in patients with cirrhosis and ascites; rifaximin did not affect glomerular filtration rate or levels of vasoactive hormones. (Hepatology 2017;65:592-603).

Low ascitic fluid total protein levels is not associated to the development of spontaneous bacterial peritonitis in a cohort of 274 patients with cirrhosis.

BACKGROUND: Spontaneous bacterial peritonitis (SBP) is a complication to decompensated cirrhosis. Fluoroquinolones may prevent SBP. However, predictive markers for SBP are wanted. Guidelines suggest that patients with ascitic fluid protein below 15 g/l receive fluoroquinolones to prevent SBP. This study aimed to assess the clinical utility of low ascitic fluid protein in predicting SBP in patients with cirrhosis and ascites. METHODS: A total of 274 patients with cirrhosis and ascites underwent paracentesis between January 2010 and June 2015. Patients were followed until two years, development of SBP, initiation of ciprofloxacin, death or liver transplantation. Data were compared between groups of patients with 'high' or 'low' ascitic protein. RESULTS: SBP developed in 31 patients (11.3%). No difference in mean ascitic fluid protein levels were found (SBP, mean: 8.5 g/l and no SBP 8.2 g/l, p = .825). SBP developed at equal rates in patients with 'high' or 'low' ascitic protein (10.8% (≤15 g/l) and 14.0% (>15 g/l), p = .599). The same trend was observed when adjusting the threshold below 10 g/l (11.9% (≤10 g/l) and 10.2% (>10 g/l), p = .697). CONCLUSIONS: Low ascitic fluid protein does not predict SBP in patients with cirrhosis and ascites. Better markers are needed.

Prognosis of patients with ascites after PleurX insertion: an observational study.

OBJECTIVE: To evaluate the safety of PleurX in cirrhotic patients with refractory ascites. METHODS: We prospectively registered patients who received a PleurX catheter cirrhosis-associated refractory ascites at our department from July 2015 to November 2016. Our control group consisted of matched cirrhotic patients with refractory ascites treated with large volume paracentesis (LVP) and patients with malignant ascites treated with PleurX during the same period. RESULTS: We included 25 patients with cirrhosis-related ascites (7 in PleurX group) and 17 with malignant ascites (14 in PleurX group). Of these, six patients had hepatocellular carcinoma and cirrhosis (5 in PleurX group). None were eligible for insertion of a TIPS or liver transplantation. The maximum duration of follow-up was (480 days) in the PleurX group and 366 days in the LVP group (median 84 and 173 days, respectively). There was no difference in mortality when comparing PleurX with LVP treatment (hazard ratios: 3.0 and 1.0, p = .23 and .96, respectively). Mortality was higher in patients with malignant ascites (p= .01). We found no significant differences in adverse events (incl. spontaneous bacterial peritonitis) or in P-albumin, P-creatinine and P-sodium between the groups. CONCLUSION: PleurX insertion for the treatment of refractory ascites in cirrhotic patients appears to be safe. Prospective randomized trials are necessary in order to confirm these findings.

Rifaximin has minor effects on bacterial composition, inflammation, and bacterial translocation in cirrhosis: A randomized trial.

BACKGROUND AND AIM: Decompensated cirrhosis is characterized by disturbed hemodynamics, immune dysfunction, and high risk of infections. Translocation of viable bacteria and bacterial products from the gut to the blood is considered a key driver in this process. Intestinal decontamination with rifaximin may reduce bacterial translocation (BT) and decrease inflammation. A randomized, placebo-controlled trial investigated the effects of rifaximin on inflammation and BT in decompensated cirrhosis. METHODS: Fifty-four out-patients with cirrhosis and ascites were randomized, mean age 56 years (± 8.4), and model for end-stage liver disease score 12 (± 3.9). Patients received rifaximin 550-mg BD (n = 36) or placebo BD (n = 18). Blood and fecal (n = 15) sampling were conducted at baseline and after 4 weeks. Bacterial DNA in blood was determined by real-time qPCR 16S rRNA gene quantification. Bacterial composition in feces was analyzed by 16S rRNA gene sequencing. RESULTS: Circulating markers of inflammation, including tumor necrosis factor alpha, interleukins 6, 10, and 18, stromal cell-derived factor 1-α, transforming growth factor ß-1, and high sensitivity C-reactive protein, were unaltered by rifaximin treatment. Rifaximin altered abundance of bacterial taxa in blood marginally, only a decrease in Pseudomonadales was observed. In feces, rifaximin decreased bacterial richness, but effect on particular species was not observed. Subgroup analyses on patients with severely disturbed hemodynamics (n = 34) or activated lipopolysaccharide binding protein (n = 37) revealed no effect of rifaximin. CONCLUSION: Four weeks of treatment with rifaximin had no impact on the inflammatory state and only minor effects on BT and intestinal bacterial composition in stable, decompensated cirrhosis (NCT01769040).

Beta-blockers in cirrhosis and refractory ascites: a retrospective cohort study and review of the literature.

OBJECTIVE: It is currently discussed if beta-blockers exert harmful effects and increase mortality in patients with cirrhosis and refractory ascites. In this study, we provide an overview of the available literature in this field in combination with a retrospective analysis of 61 patients with cirrhosis and refractory ascites in a tertiary unit. MATERIAL AND METHODS: We performed a systematic search of literature in May 2014. In addition, 61 patients with cirrhosis and ascites were identified and followed from development of refractory ascites until death or end of follow-up. RESULTS: Fourteen trials (9 trials on propranolol, 1 case-control study and 4 retrospective analyses) were identified. One trial suggested an increased mortality in patients treated with beta-blockers and refractory ascites. The results of the remaining trials were inconclusive. No increase in mortality among beta-blocker-treated patients was found in the present retrospective analysis. CONCLUSIONS: Treatment with beta-blockers may increase mortality in patients with cirrhosis and refractory ascites. However, the current evidence is sparse and high-quality studies are warranted to clarify the matter.

New vasoactive peptides in cirrhosis: organ extraction and relation to the vasodilatory state.

BACKGROUND: Patients with cirrhosis have substantial circulatory imbalance between vasoconstrictive and vasodilating forces. The study of circulatory vasoactive peptides may provide important pathophysiological information. This study aimed to assess concentrations, organ extraction and relations to haemodynamic changes in the pro-peptides copeptin, proadrenomedullin and pro-atrial natriuretic peptide (proANP) in patients with cirrhosis. MATERIALS AND METHODS: Fifty-four cirrhotic patients and 15 controls were characterized haemodynamically during a liver vein catheterization. Copeptin, proadrenomedullin and proANP were measured in hepatic and renal veins and the femoral artery. RESULTS: We found no differences in concentrations of copeptin and proadrenomedullin between patients and controls. ProANPs were higher in cirrhotic patients, median 138 pm (25/75 percentiles 101-194) compared with controls, median 91 pm (25/75 percentiles 82-153) P=0·02. ProANPs were higher in the femoral artery and renal vein, median 140 pm and 116 pm (25/75 percentiles 109-191 and 92-164, respectively), compared with controls, median 99 and 81 (25/75 percentiles 85-146 and 66-123) P=0·02 and P=0·007, respectively. We found no extraction of copeptin, proadrenomedullin or proANP over the liver. Copeptin correlated with portal pressure (R=0·50, P<0·001). Proadrenomedullin correlated with portal pressure (R=0·48, P<0·001) and heart rate (R=0·36, P<0·01). ProANP correlated with cardiac output (R=0·46, P<0·002) and portal pressure (R=0·32, P<0·02). All propeptides correlated with Child score (R>0·31, P<0·03). CONCLUSIONS: Pro-atrial natriuretic peptide is elevated in cirrhosis. Copeptin, proadrenomedullin and proANP are related to portal pressure and seem associated with systemic haemodynamics. These propeptides may participate in development and perpetuation of vasodilatation and hyperdynamic circulation in cirrhosis.

Can Plasma Volume Determination in Cirrhosis Be Replaced by an Algorithm Using Body Weight and Hematocrit?

BACKGROUND: Patients with cirrhosis often develop hyperdynamic circulation with increased cardiac output, heart rate, and redistribution of the circulating volume with expanded plasma volume (PV). PV determination is part of the evaluation of patients with cirrhosis, but gold-standard methods are invasive, expensive, and time-consuming. Therefore, other estimations of PV would be preferable, and the aim of this study was therefore to study if PV, as assessed by a simplified algorithm based on hematocrit and weight, can replace the gold-standard method. METHODS: We included 328 patients with cirrhosis who had their PV assessed by the indicator dilution technique as the gold-standard method (PVI-125). Actual PV was estimated as PVa = (1 - hematocrit)·(a + (b·body weight)). Ideal PV was estimated as PVi = c · body weight, where a, b, and c are constants. RESULTS: PVI-125, PVa, and PVi were 3.99 ± 1.01, 3.09 ± 0.54, and 3.01 ± 0.65 (Mean ± SD), respectively. Although PVI-125 correlated significantly with PVa (r = 0.72, p < 0.001), a Bland-Altman plot revealed wide limits of confidence. CONCLUSIONS: The use of simplified algorithms does not sufficiently estimate PV and cannot replace the indicator dilution technique.