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.

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.

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.