Clinical algorithms for the prevention of variceal bleeding and rebleeding in patients with liver cirrhosis

Portal hypertension(PH),a common complication of liver cirrhosis,results in development of esophageal varices.When esophageal varices rupture,they cause significant upper gastrointestinal bleeding with mortality rates up to 20%despite state-of-the-art treatment.Thus,prophylactic measures are of utmost importance to improve outcomes of patients with PH.Several high-quality studies have demonstrated that non-selective beta blockers(NSBBs)or endoscopic band ligation(EBL)are effective for primary prophylaxis of variceal bleeding.In secondary prophylaxis,a combination of NSBB+EBL should be routinely used.Once esophageal varices develop and variceal bleeding occurs,standardized treatment algorithms should be followed to minimize bleeding-associated mortality.Special attention should be paid to avoidance of overtransfusion,early initiation of vasoconstrictive therapy,prophylactic antibiotics and early endoscopic therapy.Pre-emptive transjugular intrahepatic portosystemic shunt should be used in all Child C10-C13 patients experiencing variceal bleeding,and potentially in Child B patients with active bleeding at endoscopy.The use of carvedilol,safety of NSBBs in advanced cirrhosis(i.e.with refractory ascites)and assessment of hepatic venous pressure gradient response to NSBB is discussed.In the present review,we give an overview on the rationale behind the latest guidelines and summarize key papers that have led to significant advances in the field.

Individualized treatment options for patients with non-cirrhotic and cirrhotic liver disease

The obesity pandemic has led to a significant increase in patients with metabolic dysfunction-associated fatty liver disease(MAFLD).While dyslipidemia,type 2 diabetes mellitus and cardiovascular diseases guide treatment in patients without signs of liver fibrosis,liver related morbidity and mortality becomes relevant for MAFLD’s progressive form,non-alcoholic steatohepatitis(NASH),and upon development of liver fibrosis.Statins should be prescribed in patients without significant fibrosis despite concomitant liver diseases but are underutilized in the real-world setting.Bariatric surgery,especially Y-Roux bypass,has been proven to be superior to conservative and/or medical treatment for weight loss and resolution of obesity-associated diseases,but comes at a low but existent risk of surgical complications,reoperations and very rarely,paradoxical progression of NASH.Once end-stage liver disease develops,obese patients benefit from liver transplantation(LT),but may be at increased risk of perioperative infectious complications.After LT,metabolic comorbidities are commonly observed,irrespective of the underlying liver disease,but MAFLD/NASH patients are at even higher risk of disease recurrence.Few studies with low patient numbers evaluated if,and when,bariatric surgery may be an option to avoid disease recurrence but more high-quality studies are needed to establish clear recommendations.In this review,we summarize the most recent literature on treatment options for MAFLD and NASH and highlight important considerations to tailor therapy to individual patient’s needs in light of their risk profile.

CTLA4 protects against maladaptive cytotoxicity during the differentiation of effector and follicular CD4^(+)T cells

As chronic antigenic stimulation from infection and autoimmunity is a feature of primary antibody deficiency(PAD),analysis of affected patients could yield insights into T-cell differentiation and explain how environmental exposures modify clinical phenotypes conferred by single-gene defects.CD57 marks dysfunctional T cells that have differentiated after antigenic stimulation.Indeed,while circulating CD57^(+)CD4^(+)T cells are normally rare,we found that they are increased in patients with PAD and markedly increased with CTLA4 haploinsufficiency or blockade.We performed single-cell RNA-seq analysis of matched CD57^(+)CD4^(+)T cells from blood and tonsil samples.Circulating CD57^(+)CD4^(+)T cells(CD4cyt)exhibited a cytotoxic transcriptome similar to that of CD8^(+)effector cells,could kill B cells,and inhibited B-cell responses.CTLA4 restrained the formation of CD4cyt.While CD57 also marked an abundant subset of follicular helper T cells,which is consistent with their antigen-driven differentiation,this subset had a preexhaustion transcriptomic signature marked by TCF7,TOX,and ID3 expression and constitutive expression of CTLA4 and did not become cytotoxic even after CTLA4 inhibition.Thus,CD57^(+)CD4^(+)T-cell cytotoxicity and exhaustion phenotypes are compartmentalised between blood and germinal centers.CTLA4 is a key modifier of CD4^(+)T-cell cytotoxicity,and the pathological CD4cyt phenotype is accentuated by infection.