The liver-brain axis in metabolic dysfunction-associated steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects around 30% of the global population. Studies suggest that MASLD is associated with compromised brain health and cognitive dysfunction, initiating a growing interest in exploring the liver-brain axis mechanistically within MASLD pathophysiology. With the prevalence of MASLD increasing at an alarming rate, leaving a large proportion of people potentially at risk, cognitive dysfunction in MASLD is a health challenge that requires careful consideration and awareness.

Down the road towards hepatic encephalopathy. Urea synthesis - the liver workhorse of nitrogen metabolism.

Urea synthesis is an irreversible, essential for maintenance of health and life, and highly regulated liver function with a very high capacity for production of the end-product urea-nitrogen. The set-point of urea synthesis in relation to its overall substrate, the prevailing blood concentration of L-α-amino acids, contributes to determine whole-body nitrogen balance and the size and composition of the plasma free amino acid pool. Ammonia is definitively eliminated from the body by urea synthesis.

Down the road towards hepatic encephalopathy. The elusive ammonia- what determines the arterial concentration?

Elevated arterial ammonia is associated with several complications of liver disease as it predicts mortality for in-patients and decompensation, hospitalization and death in out-patients with cirrhosis. In this review, our aim was to estimate how the individual organs contribute to arterial ammonia based on published data from human studies. The brain removes ammonia from arterial blood in a concentration-dependent fashion.

Hyperammonaemic encephalopathy due to non-functioning urea cycle as a complication to gastric bypass surgery.

Hyperammonaemic encephalopathy in the absence of liver failure is a major diagnostic challenge. A rare cause is as a complication to previous gastric bypass surgery, a condition reported to be associated with high mortality. In this case report, we present the exhaustive diagnostic work-up and clinical reversal of deep and recurrent hyperammonaemic encephalopathy in a patient with previous gastric bypass surgery.

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.

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.

Antioxidant Microgels Support Peroxide-Challenged Hepatic Cells.

Access to therapeutic strategies that counter cellular stress induced by reactive oxygen species (ROS) is an important, long-standing challenge. Here, the assembly of antioxidant artificial cells is based on alginate hydrogels equipped with non-native catalysts, namely platinum nanoparticles and an EUK compound. These artificial cells are able to preserve the viability and lower the intracellular ROS levels of challenged hepatic cells by removing peroxides from the extracellular environment.

Post-Transjugular Intrahepatic Portosystemic Shunt (TIPS) Hepatic Encephalopathy-A Review of the Past Decade's Literature Focusing on Incidence, Risk Factors, and Prophylaxis.

Transjugular intrahepatic portosystemic shunt (TIPS) is an established treatment for portal hypertension and its' complications in liver cirrhosis, yet the development of hepatic encephalopathy (HE) remains a significant concern. This review covers the reported incidence, risk factors, and management strategies for post-TIPS HE over the past decade. Incidence varies widely (7-61%), with factors like age, liver function, hyponatremia, and spontaneous portosystemic shunts influencing risk.

Management of cardiovascular risk in patients with metabolic dysfunction-associated steatotic liver disease.

The novel term Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is proposed to replace non-alcoholic fatty liver disease (NAFLD) to highlight the close association with the metabolic syndrome. MASLD encompasses patients with liver steatosis and at least one of five cardiometabolic risk factors which implies that these patients are at increased risk of cardiovascular disease (CVD). Indeed, the prevalence of CVD in MASLD patients is increased and CVD is recognized as the most common cause of death in MASLD patients.

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.

Development and validation of the AMMON-OHE model to predict risk of overt hepatic encephalopathy occurrence in outpatients with cirrhosis.

Background & Aims: Neuropsychological and psychophysical tests are recommended to assess the risk of overt hepatic encephalopathy (OHE), but their accuracy is limited. Hyperammonaemia is central in the pathogenesis of OHE, but its predictive utility is unknown. In this study, we aimed to determine the role of neuropsychological or psychophysical tests and ammonia, and to develop a model (AMMON-OHE) to stratify the risk of subsequent OHE development in outpatients with cirrhosis.

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.

Hypokalaemia - an active contributor to hepatic encephalopathy?

Patients with cirrhosis are prone to electrolyte disorders, including hypokalaemia. The available evidence suggests that hypokalaemia facilitates hyperammonaemia and thus increases the risk for hepatic encephalopathy (HE). In case studies, plasma potassium decrements were followed by plasma ammonia increments and HE progression, which was reversed by potassium supplementation.

The role of brain inflammation and abnormal brain oxygen homeostasis in the development of hepatic encephalopathy.

Hepatic encephalopathy (HE) is a frequent complication of chronic liver disease (CLD) and has a complex pathogenesis. Several preclinical and clinical studies have reported the presence of both peripheral and brain inflammation in CLD and their potential impact in the development of HE. Altered brain vascular density and tone, as well as compromised cerebral and systemic blood flow contributing to the development of brain hypoxia, have also been reported in animal models of HE, while a decrease in cerebral metabolic rate of oxygen and cerebral blood flow has consistently been observed in patients with HE.

Plasma ammonia levels predict hospitalisation with liver-related complications and mortality in clinically stable outpatients with cirrhosis.

Background & Aims: Hyperammonaemia is central in the pathogenesis of hepatic encephalopathy. It also has pleiotropic deleterious effects on several organ systems, such as immune function, sarcopenia, energy metabolism and portal hypertension. This study was performed to test the hypothesis that severity of hyperammonaemia is a risk factor for liver-related complications in clinically stable outpatients with cirrhosis.

Impaired fibrinolysis without hypercoagulability characterises patients with non-alcoholic fatty liver disease.

Introduction: Cardiovascular disease is the major cause of mortality in non-alcoholic fatty liver disease (NAFLD), a disease affecting one quarter of the world's population. Coagulation imbalance may be a contributing factor but is yet to be convincingly disclosed.

Aim: To perform an extensive mapping of the hemostatic system; primary and secondary hemostasis and the fibrinolytic system in non-diabetic NAFLD patients.

Non-alcoholic Fatty Liver Disease: Also a Disease of the Brain? A Systematic Review of the Preclinical Evidence.

Non-alcoholic fatty liver disease (NAFLD) currently affects 25% of the global adult population. Cognitive impairment is a recently recognised comorbidity impeding memory, attention, and concentration, affecting the patients' activities of daily living and reducing their quality of life. This systematic review provides an overview of the evidence for, and potential pathophysiological mechanisms behind brain dysfunction at a neurobiological level, in preclinical NAFLD.

Psychometric methods for diagnosing and monitoring minimal hepatic encephalopathy -current validation level and practical use.

Hepatic encephalopathy (HE) is cerebral dysfunction caused by liver failure and inflicts 30-40% of patients with liver cirrhosis during their disease course. Clinically manifest HE is often preceded by minimal HE (MHE) - a clinically undetectable cognitive disturbance closely associated with loss of quality of life. Accordingly, detecting and treating MHE improve the patients' daily functioning and prevent HE-related hospital admissions.

Activation and Functional Priming of Blood Neutrophils in Non-Alcoholic Fatty Liver Disease Increases in Non-Alcoholic Steatohepatitis.

Introduction: In non-alcoholic fatty liver disease (NAFLD), neutrophils in liver infiltrates are activated, which may contribute to disease progression towards non-alcoholic steatohepatitis (NASH). However, the functional status of the blood neutrophils remains unknown and their role in the disease mechanisms is thus uncertain. We therefore characterized activation and function of blood neutrophils in patients with NAFLD in relation to clinical disease markers and the NAFLD plasma milieu.

[Hyperammonaemic encephalopathy in adults without liver diseases].

Hyperammonaemic encephalopathy (HAE) in adults in the absence of acute or chronic liver disease is a severe condition caused by inborn errors of metabolism or acquired conditions like bariatric surgery, medications or malignancy as summarised in this review. Metabolic defects are most often caused by partial defects in the urea cycle enzymes demasked by stressors, whereas mechanisms underlying the acquired causes are complex and often multifactorial. Awareness of HAE and knowledge of the causes can help the clinician to deal appropriately with patients presenting with symptoms suggesting HAE and no signs of liver disease.