Alvaro, Domenico

The systemic impairment that accompanies liver cirrhosis is known to carry a significant burden on death and postoperative complications in cardiovascular interventions. This review analyzes the impact of liver cirrhosis on short‐ and long‐term outcomes after cardiac surgery and percutaneous procedures, providing an evidence‐based guidance in the decision‐making process and perioperative management of these patients. Several parameters should be considered by the heart teams when assessing eligibility, indications for intervention, and perioperative management of these patients. Life expectancy, long‐term procedural outcomes, Child–Pugh or the Model for End‐Stage Liver Disease score, presence of gastroesophageal varices and hepatic venous pressure gradient were extrapolated as the main determinants in decision making in patients with cirrhosis. Assessment and treatment of gastroesophageal varices is mandatory. Hepatic venous pressure gradient values >20 mm Hg preclude patients from a surgical approach. Considering the poor prognosis of advanced liver cirrhosis, futile treatments should be avoided. A multidimensional heart team approach involving surgical, cardiologic, anesthesiologic, hepatological, and medical considerations is recommended.

AbstractBackground & AimsMachine learning (ML) provides new approaches for prognostication through the identification of novel subgroups of patients. We explored whether ML could support disease sub‐phenotyping and risk stratification in primary biliary cholangitis (PBC).MethodsML was applied to an international dataset of PBC patients. The dataset was split into a derivation cohort (training set) and a validation cohort (validation set), and key clinical features were analysed. The outcome was a composite of liver‐related death or liver transplantation. ML and standard survival analysis were performed.ResultsThe training set was composed of 11,819 subjects, while the validation set was composed of 1,069 subjects. ML identified four clusters of patients characterized by different phenotypes and long‐term prognosis. Cluster 1 (n = 3566) included patients with excellent prognosis, whereas Cluster 2 (n = 3966) consisted of individuals at worse prognosis differing from Cluster 1 only for albumin levels around the limit of normal. Cluster 3 (n = 2379) included young patients with florid cholestasis and Cluster 4 (n = 1908) comprised advanced cases. Further sub‐analyses on the dynamics of albumin within the normal range revealed that ursodeoxycholic acid‐induced increase of albumin >1.2 x lower limit of normal (LLN) is associated with improved transplant‐free survival.ConclusionsUnsupervised ML identified four novel groups of PBC patients with different phenotypes and prognosis and highlighted subtle variations of albumin within the normal range. Therapy‐induced increase of albumin >1.2 x LLN should be considered a treatment goal.

Objective Primary sclerosing cholangitis (PSC) is a genetically complex, inflammatory bile duct disease of largely unknown aetiology often leading to liver transplantation or death. Little is known about the genetic contribution to the severity and progression of PSC. The aim of this study is to identify genetic variants associated with PSC disease progression and development of complications. Design We collected standardised PSC subphenotypes in a large cohort of 3402 patients with PSC. After quality control, we combined 130 422 single nucleotide polymorphisms of all patients—obtained using the Illumina immunochip—with their disease subphenotypes. Using logistic regression and Cox proportional hazards models, we identified genetic variants associated with binary and time-to-event PSC subphenotypes. Results We identified genetic variant rs853974 to be associated with liver transplant-free survival (p=6.07×10–9). Kaplan-Meier survival analysis showed a 50.9% (95% CI 41.5% to 59.5%) transplant-free survival for homozygous AA allele carriers of rs853974 compared with 72.8% (95% CI 69.6% to 75.7%) for GG carriers at 10 years after PSC diagnosis. For the candidate gene in the region, RSPO3, we demonstrated expression in key liver-resident effector cells, such as human and murine cholangiocytes and human hepatic stellate cells. Conclusion We present a large international PSC cohort, and report genetic loci associated with PSC disease progression. For liver transplant-free survival, we identified a genome-wide significant signal and demonstrated expression of the candidate gene RSPO3 in key liver-resident effector cells. This warrants further assessments of the role of this potential key PSC modifier gene.