Clearance and production of ammonia quantified in humans by constant ammonia infusion - the effects of cirrhosis and ammonia-targeting treatments.

BACKGROUND & AIMS: Hyperammonaemia is a key pathological feature of liver disease and the primary driver of hepatic encephalopathy (HE). However, the relative roles of increased ammonia production and reduced clearance are poorly understood as is the action of ammonia-targeting drugs for HE. We aimed to quantify whole-body ammonia metabolism in healthy persons and patients with cirrhosis and to validate our method by examining the effects of glycerol phenylbutyrate and lactulose + rifaximin treatment. METHODS: Ten healthy men and ten male patients with cirrhosis were investigated by 90-minute constant ammonia infusion to achieve steady-state plasma ammonia. Whole-body ammonia clearance was calculated as infusion rate divided by steady-state concentration increase and ammonia production was calculated as clearance multiplied by baseline ammonia concentration. Participants were re-investigated after the ammonia-targeting interventions. RESULTS: In healthy persons, ammonia clearance was 3.5 (3.1-3.9) L/min and ammonia production was 49 (35-63) µmol/min. Phenylbutyrate increased clearance by 11% (4-19%, p = 0.009). In patients with cirrhosis, ammonia clearance was 20% lower at 2.7 (2.1-3.3) L/min (p = 0.02) and production was nearly threefold higher at 131 (102-159) µmol/min (p <0.0001). Lactulose + rifaximin reduced production by 20% (2-37%, p = 0.03). The infusion was generally well-tolerated apart from in one hyperammonaemic patient, with cirrhosis and possible bleeding unrelated to the infusion, who developed clinical HE that reverted when infusion was discontinued. CONCLUSIONS: Whole-body ammonia clearance and production may be measured separately using the described technique. This technique identified a lower clearance and a higher production of ammonia in patients with cirrhosis, and showed that phenylbutyrate increases clearance, whereas lactulose + rifaximin reduces production. IMPACT AND IMPLICATIONS: High blood ammonia plays a key role in cirrhosis-related brain dysfunction. However, the relative roles of reduced ammonia clearance and increased ammonia production are poorly understood as is the action of ammonia-targeting treatments. This study presents a relatively simple test to measure ammonia metabolism. By using this test, it was possible to show that patients with cirrhosis exhibit decreased ammonia clearance and increased ammonia production compared to healthy persons, and to quantify the unique effects of different ammonia-targeting treatments. The test described herein may be used to examine a range of questions related to normal physiology, pathophysiology and the mechanisms of action of ammonia-targeting treatments. CLINICAL TRIAL NUMBER: ClinicalTrials.gov (1-16-02-297-20).

The presence of interferon affects the progression of non-alcoholic fatty liver disease.

Inflammation and metabolic dysfunction are hallmarks of the progression of non-alcoholic fatty liver disease (NAFLD), which is the fastest-growing liver disease worldwide. Emerging evidence indicates that innate immune mechanisms are essential drivers of fibrosis development in chronic inflammatory liver diseases, including NAFLD. In this study, 142 NAFLD patients were genotyped for three IFNL4 single-nucleotide variants in order to investigate the genetic relationship between IFNL4 and fibrosis in NAFLD patients. We observed an overrepresentation of the non-functional IFNL4 allele in patients with significant fibrosis (>F2). Next, we investigated the potential protective role of interferon (IFN) in relation to the development of liver fibrosis in an animal model of non-alcoholic steatohepatitis (NASH). In contradiction to our hypothesis, the results showed an increase in fibrosis in IFN treated animals. Our study clearly indicates that IFN is able to affect the development of liver fibrosis, although our clinical and experimental data are conflicting.

Experimental non-alcoholic fatty liver disease causes regional liver functional deficits as measured by the capacity for galactose metabolism while whole liver function is preserved.

BACKGROUND: Increasing incidence of non-alcoholic fatty liver disease (NAFLD) calls for improved understanding of how the disease affects metabolic liver function. AIMS: To investigate in vivo effects of different NAFLD stages on metabolic liver function, quantified as regional and total capacity for galactose metabolism in a NAFLD model. METHODS: Male Sprague Dawley rats were fed a high-fat, high-cholesterol diet for 1 or 12 weeks, modelling early or late NAFLD, respectively. Each NAFLD group (n = 8 each) had a control group on standard chow (n = 8 each). Metabolic liver function was assessed by 2-[18F]fluoro-2-deoxy-D-galactose positron emission tomography; regional galactose metabolism was assessed as standardised uptake value (SUV). Liver tissue was harvested for histology and fat quantification. RESULTS: Early NAFLD had median 18% fat by liver volume. Late NAFLD had median 32% fat and varying features of non-alcoholic steatohepatitis (NASH). Median SUV reflecting regional galactose metabolism was reduced in early NAFLD (9.8) and more so in late NAFLD (7.4; p = 0.02), both significantly lower than in controls (12.5). In early NAFLD, lower SUV was quantitatively explained by fat infiltration. In late NAFLD, the SUV decrease was beyond that attributable to fat; probably related to structural NASH features. Total capacity for galactose elimination was intact in both groups, which in late NAFLD was attained by increased fat-free liver mass to 21 g, versus 15 g in early NAFLD and controls (both p ≤ 0.002). CONCLUSION: Regional metabolic liver function was compromised in NAFLD by fat infiltration and structural changes. Still, whole liver metabolic function was preserved in late NAFLD by a marked increase in the fat-free liver mass.

Early normalization of reduced urea synthesis capacity after direct-acting antiviral therapy in hepatitis C cirrhosis.

Laursen TL, Sandahl TD, Kazankov K, Eriksen PL, Kristensen LH, Holmboe CH, Laursen AL, Vilstrup H, Grønbæk H. Early normalization of reduced urea synthesis capacity after direct-acting antiviral therapy in hepatitis C cirrhosis. Am J Physiol Gastrointest Liver Physiol 319: G151-G156, 2020. First published June 29, 2020; doi:10.1152/ajpgi.00128.2020.-Effects of direct-acting antiviral (DAA) treatment of chronic hepatitis C (CHC) cirrhosis on metabolic liver function are unknown but important for prognosis. Ureagenesis is an essential metabolic liver function involved in whole body nitrogen homeostasis. We aimed to investigate the ureagenesis capacity before and immediately after DAA therapy and relate the findings to hepatic inflammation and structural changes. In an observational before-and-after intervention study, the ureagenesis capacity was quantified by functional hepatic nitrogen clearance (FHNC) in 9 CHC patients with cirrhosis and 10 healthy volunteers. Hepatic inflammation was evaluated by alanine aminotransferase (ALT) and the macrophage activation markers sCD163 and sMR. Structural changes were estimated as liver stiffness and by portal hypertension as the hepatic venous pressure gradient (HVPG). Before treatment, the FHNC in the patients was half of the controls [16.4 L/h (8.2-24.5) vs. 33.4 (29.2-37.6), P = 0.0004]; after successful DAA treatment, it normalized [28.4 (15.9-40.9), P = 0.008 vs. baseline]. DAA treatment normalized ALT (P < 0.0001) and decreased the elevated sCD163 from 5.6 mg/L (3.5-7.7) to 3.4 (2-0-4.8) (P < 0.001) and sMR from 0.35 mg/L (0.21-0.49) to 0.31 (0.17-0.45) (P < 0.01). Liver stiffness fell by 30% (P < 0.05) but remained over the cirrhosis threshold. HVPG was not affected (P = 0.59). DAA treatment restored the severely reduced ureagenesis capacity, along with amelioration of hepatic inflammation but without normalization of other cirrhosis characteristics. Our findings indicate that the anti-inflammatory effect of virus eradication independent of hepatic structural effects rapidly improves metabolic dysfunction. We suggest this effect to be an important early onset part of the expected clinical DAA treatment benefit.NEW & NOTEWORTHY Antiviral treatment of chronic hepatitis C restores the liver's reduced capacity to produce urea along with an improvement in liver inflammation without immediate effects on structural liver changes. The effect is suggested to be an important early onset part of the expected clinical treatment benefit.

A systematic review and meta-analysis of endovascular versus open surgical repair for the traumatic ruptured thoracic aorta.

OBJECTIVE: The purpose of this study was to compare clinical outcomes between open repair and thoracic endovascular aortic repair (TEVAR) in traumatic ruptured thoracic aorta. METHODS: A comprehensive search was undertaken of the four major databases (PubMed, Embase, Scopus, and Ovid) to identify all published data comparing open vs endovascular repair. Databases were evaluated to July 2018. Odds ratios (ORs), weighted mean differences, or standardized mean differences and their 95% confidence intervals (CIs) were analyzed. The primary outcomes were stroke, paraplegia, and 30-day mortality rates; secondary outcomes were requirement for reintervention and 1-year and five-year mortality rates. RESULTS: A total of 1968 patients were analyzed in 21 articles. TEVAR was performed in 29% (n = 578) and open repair in 71% (n = 1390). TEVAR and open repair did not differ in the mean age of patients (42.1 ± 14 years vs 44.1 ± 14 years; P = .48). There was no difference in duration of intensive care and total hospital stay between TEVAR and open repair groups (12.7 ± 11.1 days vs 12.6 ± 8 days [P = .35] and 27.5 ± 14.6 days vs 25.9 ± 11 days [P = .80], respectively). Similarly, no statistically significant difference in postoperative paraplegia or stroke rate was noted between TEVAR and open repair (1.4% vs 2.3% [OR, 1.27; 95% CI, 0.59-2.70; P = .54] and 1% vs 0.5% [OR, 0.63; 95% CI, 0.18-2.18; P = .46]). Lower 30-day and 1-year mortality was noted in TEVAR (7.9% vs 20% [OR, 2.94; 95% CI, 1.92-4.49; P < .00001] and 8.7% vs 17% [OR, 2.11; 95% CI, 0.99-4.52; P = .05]). There was no difference in 5-year mortality (23% vs 17%; OR, 0.07; 95% CI, -0.07 to 0.20; P = .33). However, there was a higher rate of reintervention at 1 year in the endovascular group (0% vs 6%; OR, 0.17; 95% CI, 0.03-0.96; P = .04). CONCLUSIONS: TEVAR carries lower in-hospital mortality and provides satisfactory perioperative outcomes compared with open repair in traumatic ruptured thoracic aorta. It also provides a favorable 1-year survival at the expense of higher reintervention rates.

Human translatability of the GAN diet-induced obese mouse model of non-alcoholic steatohepatitis.

BACKGROUND: Animal models of non-alcoholic steatohepatitis (NASH) are important tools in preclinical research and drug discovery. Gubra-Amylin NASH (GAN) diet-induced obese (DIO) mice represent a model of fibrosing NASH. The present study directly assessed the clinical translatability of the model by head-to-head comparison of liver biopsy histological and transcriptome changes in GAN DIO-NASH mouse and human NASH patients. METHODS: C57Bl/6 J mice were fed chow or the GAN diet rich in saturated fat (40%), fructose (22%) and cholesterol (2%) for ≥38 weeks. Metabolic parameters as well as plasma and liver biomarkers were assessed. Liver biopsy histology and transcriptome signatures were compared to samples from human lean individuals and patients diagnosed with NASH. RESULTS: Liver lesions in GAN DIO-NASH mice showed similar morphological characteristics compared to the NASH patient validation set, including macrosteatosis, lobular inflammation, hepatocyte ballooning degeneration and periportal/perisinusoidal fibrosis. Histomorphometric analysis indicated comparable increases in markers of hepatic lipid accumulation, inflammation and collagen deposition in GAN DIO-NASH mice and NASH patient samples. Liver biopsies from GAN DIO-NASH mice and NASH patients showed comparable dynamics in several gene expression pathways involved in NASH pathogenesis. Consistent with the clinical features of NASH, GAN DIO-NASH mice demonstrated key components of the metabolic syndrome, including obesity and impaired glucose tolerance. CONCLUSIONS: The GAN DIO-NASH mouse model demonstrates good clinical translatability with respect to the histopathological, transcriptional and metabolic aspects of the human disease, highlighting the suitability of the GAN DIO-NASH mouse model for identifying therapeutic targets and characterizing novel drug therapies for NASH.

Local Versus General Anesthesia in Nonemergency Endovascular Abdominal Aortic Aneurysm Repair: A Systematic Review and Meta-Analysis.

The purpose of this systematic review was to assess the perioperative clinical outcomes in using local/regional anesthesia (LA/RA) or general anesthesia (GA) in patients undergoing endovascular abdominal aortic aneurysm repair. A comprehensive electronic literature search was undertaken from inception to September 2018, identifying all randomized and nonrandomized studies comparing LA/RA versus GA in patients with abdominal aortic aneurysm who underwent endovascular repair. A total of 12,024 patients (n = 1,664 LA/RA, n = 10,360 GA) were analyzed from 12 observational studies included in this analysis. No difference in mean age between LA/RA and GA group was noted (73.8 ± 7.8 y v 72.4 ± 7.6 y, 95% confidence interval 0.85 [-0.08 to 1.79]; p = 0.07). No differences in preoperative rate of chronic obstructive pulmonary disease, ischemic heart disease, diabetes mellitus, and American Society of Anesthesiologists grades were noted between the 2 groups (p = 0.21, p = 0.85, p = 0.46, and p = 0.67, respectively). Shorter total surgical time in LA/RA patients was reported (135 ± 40 min v 164 ± 43 min; p < 0.00001). Shorter hospital stay was observed in LA/RA patients (3.6 ± 3.3 d v 4.6 ± 5 d; p = 0.002). No difference in cardiac or renal complications was noted between the LA/RA and GA groups postoperatively (2.7% v 2.5%; p = 0.46 and 1.2% v 1.6%; p = 0.13). Similarly, no difference in vascular complications was noted in LA/RA versus GA patients (8.4% v 7.7%; p = 0.44). Thirty-day morality was not different between the 2 cohorts (2% v 1.7%; p = 0.97). Use of LA/RA in selective endovascular abdominal aortic aneurysm repair procedures provides satisfactory and comparable perioperative outcomes with those of GA, with the advantage of a shorter hospital stay. A large randomized controlled trial or multicenter study is required to confirm the present study's findings.

The Future of Open Heart Surgery in the Era of Robotic and Minimal Surgical Interventions.

It has been over two decades since the very first robotic cardiac surgery was performed. Over the years, there has been an increase in the demand for less invasive cardiac surgical techniques. Developments in technology and engineering have provided an opportunity for robotic surgery to be applied to a variety of cardiac procedures, including coronary revascularisation, mitral valve surgery, atrial fibrillation ablation, and others. In coronary revascularisation, it is becoming more widely used in single vessel, as well as hybrid coronary artery approaches. Currently, several international centres are specialising in a totally endoscopic coronary artery bypass surgery involving multiple vessels. Mitral valve and other intracardiac pathologies such as atrial septal defect and intracardiac tumour are also increasingly being addressed robotically. Even though some studies have shown good results with robot-assisted cardiac surgery, there are still concerns about safety, cost and clinical efficacy. There are also limitations and additional challenges with the management of cardiopulmonary bypass and myocardial protection during robotic surgery. Implementing novel strategies to manage these challenges, together with careful patient selection can go a long way to producing satisfactory results. This review examines the current evidence behind robotic surgery in various aspects of cardiac surgery.

Perturbations of urea cycle enzymes during posthepatectomy rat liver failure.

Posthepatectomy liver failure (PHLF) may occur after extended partial hepatectomy (PH). If malignancy is widespread in the liver, the size of PH and hence the size of the future liver remnant (FLR) may limit curability. We aimed to characterize differences in protein expression between different sizes of FLRs and identify proteins specific to the regenerative process of minimal-size FLR (MSFLR), with special focus on postoperative day (POD) 1 when PHLF is present. A total of 104 male Wistar rats were subjected to 30, 70, or 90% PH (MSFLR in rats), sham operation, or no operation. Blood and liver tissue were harvested at POD1, 3, and 5 (n = 8 per group). Protein expression was assessed by proteomic profiling by unsupervised two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) liquid chromatography tandem mass spectrometry (LC-MS/MS), followed by supervised selected reaction monitoring (SRM)-MS/MS. In all, 1,035 protein spots were detected, 54 of which were significantly differentially expressed between groups and identifiable. During PHLF after PH(90%) at POD1, urea cycle and related proteins showed significant perturbations, including the urea cycle flux-regulating enzyme of carbamoyl phosphate synthase-1, ornithine transcarbamylase, and arginase-1, as well as the ornithine aminotransferase and propionyl-CoA carboxylase alpha chain. Plasma-ammonia increased significantly at POD1 after PH(90%), followed by a prompt decrease. At the protein level, we found perturbations of urea cycle and related enzymes in the MSFLR during PHLF. Our results suggest that these perturbations may augment urea cycle function, which may be pivotal for increased ammonia elimination after extensive PHs and potential PHLF.NEW & NOTEWORTHY Posthepatectomy liver failure (PHLF) is associated with high mortality. In a rat model of 90% hepatectomy, PHLF is present. Our results on liver tissue proteomics suggest that the ability of the liver remnant to sufficiently eliminate ammonia may be brought about by perturbation related to urea cycle proteins and that enhancing the urea cycle capacity may play a key role in surviving PHLF.

Hepatic transcriptome signatures in patients with varying degrees of nonalcoholic fatty liver disease compared with healthy normal-weight individuals.

Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of conditions ranging from simple steatosis (NAFL), over nonalcoholic steatohepatitis (NASH) with or without fibrosis, to cirrhosis with end-stage disease. The hepatic molecular events underlying the development of NAFLD and transition to NASH are poorly understood. The present study aimed to determine hepatic transcriptome dynamics in patients with NAFL or NASH compared with healthy normal-weight and obese individuals. RNA sequencing and quantitative histomorphometry of liver fat, inflammation and fibrosis were performed on liver biopsies obtained from healthy normal-weight ( n = 14) and obese ( n = 12) individuals, NAFL ( n = 15) and NASH ( n = 16) patients. Normal-weight and obese subjects showed normal liver histology and comparable gene expression profiles. Liver transcriptome signatures were largely overlapping in NAFL and NASH patients, however, clearly separated from healthy normal-weight and obese controls. Most marked pathway perturbations identified in both NAFL and NASH were associated with markers of lipid metabolism, immunomodulation, extracellular matrix remodeling, and cell cycle control. Interestingly, NASH patients with positive Sonic hedgehog hepatocyte staining showed distinct transcriptome and histomorphometric changes compared with NAFL. In conclusion, application of immunohistochemical markers of hepatocyte injury may serve as a more objective tool for distinguishing NASH from NAFL, facilitating improved resolution of hepatic molecular changes associated with progression of NAFLD. NEW & NOTEWORTHY Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in Western countries. NAFLD is associated with the metabolic syndrome and can progress to the more serious form, nonalcoholic steatohepatitis (NASH), and ultimately lead to irreversible liver damage. Using gold standard molecular and histological techniques, this study demonstrates that the currently used diagnostic tools are problematic for differentiating mild NAFLD from NASH and emphasizes the marked need for developing improved histological markers of NAFLD progression.

Non-alcoholic fatty liver disease alters expression of genes governing hepatic nitrogen conversion.

BACKGROUND & AIMS: We recently showed that the functional capacity for ureagenesis is deficient in non-alcoholic fatty liver disease (NAFLD) patients. The aim of this study was to assess expression of urea cycle-related genes to elucidate a possible gene regulatory basis to the functional problem. METHODS: Liver mRNA expression analyses within the gene pathway governing hepatic nitrogen conversion were performed in 20 non-diabetic, biopsy-proven NAFLD patients (8 simple steatosis; 12 non-alcoholic steatohepatitis [NASH]) and 12 obese and 14 lean healthy individuals. Sixteen NAFLD patients were included for gene expression validation. Relationship between gene expressions and functional capacity for ureagenesis was described. RESULTS: Gene expression of most urea cycle-related enzymes were downregulated in NAFLD vs both control groups; markedly so for the urea cycle flux-generating carbamoyl phosphate synthetase (CPS1) (~3.5-fold, P < .0001). In NASH, CPS1 downregulation paralleled the deficit in ureagenesis (P = .03). Additionally, expression of several genes involved in amino acid uptake and degradation, and the glucagon receptor gene, were downregulated in NAFLD. Conversely, glutamine synthetase (GS) expression increased >1.5-fold (P ≤ .03), inversely related to CPS1 expression (P = .004). CONCLUSIONS: NAFLD downregulated the expression of urea cycle-related genes. Downregulation of urea cycle flux-generating CPS1 correlated with the loss of functional capacity for ureagenesis in NASH. On gene level, these changes coincided with an increase in the major ammonia scavenging enzyme GS. The effects seemed related to a fatty liver as such rather than NASH or obesity. The findings support gene regulatory mechanisms involved in the deficient ureagenesis of NAFLD, but it remains unexplained how hepatocyte fat accumulation exerts these effects.

Men with biopsy-confirmed hepatocellular adenoma have a high risk of progression to hepatocellular carcinoma: A nationwide population-based study.

BACKGROUND & AIMS: Hepatocellular adenoma is a benign liver tumour that may transform to hepatocellular carcinoma (HCC). We used data from Danish nationwide healthcare registries to investigate the incidence and prognosis of hepatocellular adenoma. METHODS: We included all patients with a hospital discharge diagnosis for benign liver tumour (ICD-10: D13.4) in 1997-2012 and a liver biopsy confirming the hepatocellular adenoma diagnosis. Follow-up began 1 year after adenoma diagnosis, to minimise the possibility that the tumour was a misdiagnosed HCC. All patients were age- and gender-matched with 50 random controls from the Danish population. We followed patients and controls with respect to HCC development, adenoma resection, and death without HCC (ie, death without having been diagnosed with HCC) through 2013. HCC diagnoses were identified in the Danish Cancer Registry. RESULTS: We included 67 patients with hepatocellular adenoma, and 58 (87%) were women. The overall incidence rate of histologically verified hepatocellular adenoma in the Danish general population was 0.07 (95% CI: 0.06-0.09) per 100 000 population per year. Fifteen patients had their adenoma resected before follow-up began, leaving 52 patients for follow-up. Men with biopsy-confirmed hepatocellular adenoma had a 10-year cumulative HCC risk as high as 60.0% (95% CI: 15.3%-87.0%). All men who developed HCC were older than 50 years at adenoma diagnosis. By contrast, none of the 44 women in the follow-up analysis developed HCC. CONCLUSION: Histologically verified hepatocellular adenoma is rare in Denmark. It is a minor concern for women, but men have a very high risk of progression to HCC.

Severe hepatic cholestasis after treatment with amoxicillin/clavulanic acid.

Amoxicillin/clavulanate is a commonly used antibiotic. Though relatively rare, amoxicillin/clavulanate carries the highest incidence of idiosyncratic drug-induced liver disease. This case report presents an 80-year-old woman treated for simple respiratory tract infection with amoxicillin/clavulanate who was subsequently hospitalized with malaise and icterus and a biochemical cholestatic pattern with high alkaline phosphatase and bilirubin. Diagnostically challenging, ultimately, liver biopsy revealed drug-induced liver injury with a fatal course after attempt of supportive, symptomatic treatment.

Cerebral Aspects of Portal Hypertension: Hepatic Encephalopathy.

Portal hypertension has cerebral consequences via its causes and complications, namely hepatic encephalopathy (HE), a common and devastating brain disturbance caused by liver insufficiency and portosystemic shunting. The pathogenesis involves hyperammonemia and systemic inflammation. Symptoms are disturbed personality and reduced attention. HE is minimal or grades I to IV (coma). Bouts of HE are episodic and often recurrent. Initial treatment is of events that precipitated the episode and exclusion of nonhepatic causes. Specific anti-HE treatment is lactulose. By recurrence, rifaximin is add-on. Anti-HE treatment is efficacious also for prophylaxis, but emergence of HE marks advanced liver disease and a dismal prognosis.

Cognitive dysfunction in early experimental metabolic dysfunction-associated steatotic liver disease is associated with systemic inflammation and neuroinflammation.

Background & Aims: Cognitive dysfunction is an increasingly recognised manifestation of metabolic dysfunction-associated steatotic liver disease (MASLD), but the mechanistic link remains unclear. The aim of this study was to investigate the hypothesis that experimental MASLD leads to cognitive dysfunction via systemic inflammation and neuroinflammation. Methods: Twenty male Sprague Dawley rats were randomised to a high-fat high-cholesterol (HFHC) diet to induce MASLD, or a standard diet (n = 10/group), for 16 weeks. Assessments included: MASLD severity (histology), neurobehaviour, inflammation (liver, plasma and cerebrospinal fluid), brain microglia and astrocyte activation, and synaptic density. Results: The HFHC diet induced MASLD with extensive steatosis and lobular inflammation without fibrosis. Several plasma cytokines were elevated (CXCL1, IL-6, IL-17, MIP-1α, MCP-1, IL-10; all p <0.05) and correlated with increases in hepatic chemokine gene expression. Cerebrospinal fluid concentrations of CXCL1 were elevated (p = 0.04). In the prefrontal brain cortex, we observed a 19% increase in microglial activation confirmed by Iba1 immunohistochemistry (p = 0.03) and 3H-PK11195 autoradiography (p <0.01). In parallel, synaptic density was reduced to 92%, assessed by 3H-UCB-J autoradiography (p <0.01). MASLD animals exhibited impaired memory to previously encountered objects in the novel object recognition test (p = 0.047) and showed depression-like behaviour evidenced by increased immobility time (p <0.01) and reduced swimming time (p = 0.03) in the forced swim test. Conclusions: Experimental non-fibrotic MASLD, as a model to reflect the early stage of human disease, results in cognitive impairment and depression-like behaviour. This is associated with an inflammatory phenotype not only in the liver but also in the plasma and brain, which together with diminished synaptic density, provides a pathophysiological link between liver disease and cognitive dysfunction in MASLD. Impact and implications: Cognitive dysfunction is an increasingly recognised comorbidity in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), yet the underlying mechanisms remain unclear. This study provides evidence of impaired memory and depression-like symptoms in early experimental MASLD and indicates that hepatic inflammation may drive a systemic inflammatory response, resulting in neuroinflammation and reduced brain synaptic density. The evidence of impaired memory in MASLD and establishing its underlying pathophysiological link provides insights that could guide the development of potential new treatments for this increasingly common condition in people of working age. The study also emphasises the need to develop better tools for clinical cognitive testing, which will enable physicians to assess and manage brain dysfunction early in MASLD.

Role of ammonia in NAFLD: An unusual suspect.

Mechanistically, the symptomatology and disease progression of non-alcoholic fatty liver disease (NAFLD) remain poorly understood, which makes therapeutic progress difficult. In this review, we focus on the potential importance of decreased urea cycle activity as a pathogenic mechanism. Urea synthesis is an exclusive hepatic function and is the body's only on-demand and definitive pathway to remove toxic ammonia. The compromised urea cycle activity in NAFLD is likely caused by epigenetic damage to urea cycle enzyme genes and increased hepatocyte senescence. When the urea cycle is dysfunctional, ammonia accumulates in liver tissue and blood, as has been demonstrated in both animal models and patients with NAFLD. The problem may be augmented by parallel changes in the glutamine/glutamate system. In the liver, the accumulation of ammonia leads to inflammation, stellate cell activation and fibrogenesis, which is partially reversible. This may be an important mechanism for the transition of bland steatosis to steatohepatitis and further to cirrhosis and hepatocellular carcinoma. Systemic hyperammonaemia has widespread negative effects on other organs. Best known are the cerebral consequences that manifest as cognitive disturbances, which are prevalent in patients with NAFLD. Furthermore, high ammonia levels induce a negative muscle protein balance leading to sarcopenia, compromised immune function and increased risk of liver cancer. There is currently no rational way to reverse reduced urea cycle activity but there are promising animal and human reports of ammonia-lowering strategies correcting several of the mentioned untoward aspects of NAFLD. In conclusion, the ability of ammonia-lowering strategies to control the symptoms and prevent the progression of NAFLD should be explored in clinical trials.

Transcatheter Aortic Valve Implantation in Bicuspid Aortic Valve with Aortic Stenosis: a Meta-Analysis and Trial Sequential Analysis.

OBJECTIVES: Bicuspid aortic valve (BAV) is an important aetiology of aortic stenosis and the use of transcatheter aortic valve implantation (TAVI) has not been fully explored in this cohort. This systematic review and meta-analysis compared the outcomes of TAVI in stenotic BAV against tricuspid aortic valve (TAV). METHODS: An electronic literature search was performed in PubMed, MEDLINE, EMBASE, and Scopus to identify all studies comparing TAVI in stenotic BAV versus TAV. Only studies comparing TAVI in BAV versus TAV were included, without any limit on the study date. Primary endpoints were 30-day and 1-year mortality, while secondary endpoints were postoperative rates of stroke, acute kidney injury (AKI), and permanent pacemaker (PPM) requirement. A trial sequential analysis (TSA) was performed for all endpoints to understand their significance. RESULTS: Thirteen studies met the inclusion criteria (917 BAV and 3079 TAV patients). The BAV cohort was younger (76.8±7.43 years vs. 78.5±7.12 years, P=0.02), had a higher trans-aortic valve gradient (P=0.02), and larger ascending aortic diameters (P<0.0001). No significant difference was shown for primary (30-day mortality [P=0.45] and 1-year mortality [P=0.41]) and secondary endpoints (postoperative stroke [P=0.49], AKI [P=0.14], and PPM requirement [P=0.86]). The BAV group had a higher rate of significant postoperative aortic regurgitation (P=0.002). TSA showed that there was sufficient evidence to conclude the lack of difference in PPM requirements, and 30-day and 1-year mortality between the two cohorts. CONCLUSION: TAVI gives satisfactory outcomes for treating stenotic BAV and should be considered clinically.