Validation of a Model for Identification of Patients With Compensated Cirrhosis at High Risk of Decompensation.

BACKGROUND & AIMS: It is important to rapidly identify patients with advanced liver disease. Routine tests to assess liver function and fibrosis provide data that can be used to determine patients' prognoses. We tested the validated the ability of combined data from the ALBI and FIB-4 scoring systems to identify patients with compensated cirrhosis at highest risk for decompensation. METHODS: We collected data from 145 patients with compensated cirrhosis (91% Child A cirrhosis and median MELD scores below 8) from a cohort in Nottingham, United Kingdom, followed for a median 4.59 years (development cohort). We collected baseline clinical features and recorded decompensation events. We used these data to develop a model based on liver function (assessed by the ALBI score) and extent of fibrosis (assessed by the FIB-4 index) to determine risk of decompensation. We validated the model in 2 independent external cohorts (1 in Dublin, Ireland and 1 in Menoufia, Egypt) comprising 234 patients. RESULTS: In the development cohort, 19.3% of the patients developed decompensated cirrhosis. Using a combination of ALBI and FIB-4 scores, we developed a model that identified patients at low vs high risk of decompensation (hazard ratio [HR] for decompensation in patients with high risk score was 7.10). When we tested the scoring system in the validation cohorts, the HR for decompensation in patients with a high-risk score was 12.54 in the Ireland cohort and 5.10 in the Egypt cohort. CONCLUSION: We developed scoring system, based on a combination of ALBI and FIB-4 scores, that identifies patients at risk for liver decompensation. We validated the scoring system in 2 independent international cohorts (Europe and the Middle East), so it appears to apply to diverse populations.

Increased soluble GPVI levels in cirrhosis: evidence for early in vivo platelet activation.

Cirrhosis is a consequence of prolonged liver injury and is characterised by extensive tissue fibrosis: the deposition of collagen-rich extracellular matrix. The haemostatic balance is disordered in cirrhosis and coagulation activation appears to promote fibrosis. In spite of recent studies demonstrating a role for anticoagulant therapy in preventing cirrhosis progression, there has not been a change in clinical practice, suggesting that physicians are reluctant to anticoagulate patients with cirrhosis due to bleeding risks. Platelets play an important role in facilitating coagulation. Glycoprotein VI (GPVI) is a platelet-specific collagen receptor that is shed from the platelet surface in a metalloproteinase-dependent manner in response to GPVI ligation and coagulation activation. Our aim was to use soluble GPVI levels to determine whether there was evidence for collagen and coagulation-induced platelet activation in early, well-compensated cirrhosis. Plasma soluble GPVI levels were quantified in 46 patients with mixed aetiology cirrhosis and 55 healthy controls using an immunoassay. In the cirrhosis group, soluble GPVI levels were significantly increased (5.8 ± 4.4 ng/ml, n = 46) compared to healthy controls (3.3 ± 3.4 ng/ml, n = 55, p < 0.05). This increase in soluble GPVI levels was still evident when levels were adjusted for platelet count (Healthy controls; 0.015 ± 0.018 ng/106 platelets/ml vs. cirrhosis; 0.048 ± 0.04 ng/106 platelets/ml, p < 0.0001). This study provides evidence for early platelet activation in patients with well-compensated cirrhosis. This may have translational implications for prognosis, treatment, and risk stratification.

Liver stiffness and thrombin generation in compensated cirrhosis.

BACKGROUND: Decompensated cirrhosis is associated with coagulation abnormalities that can increase the risk of thrombosis and bleeding. It is unclear precisely when these abnormalities arise and whether they are exacerbated as compensated cirrhosis progresses. Transient elastography using FibroScan generates liver stiffness measurements (LSM) that associate with portal hypertension, clinical outcomes and provides prognostic information at an earlier stage than traditional liver function scores eg, MELD score. OBJECTIVE: To characterize thrombin generation in patients with compensated cirrhosis and to determine whether parameters of coagulation change throughout compensated cirrhosis, staged using LSM. PATIENTS/METHODS: Blood samples were collected from well-compensated cirrhotic patients n = 61, All Child Pugh A stage) attending the Mater Misericordiae University Hospital, Ireland. Comprehensive clinical staging of liver disease, including LSM, was performed. Tissue Factor-stimulated thrombin generation was measured by calibrated automated thrombography. RESULTS: Using LSM to stage well-compensated cirrhotic patients, we demonstrate a significant decrease in the rate of propagation, the rate of attenuation, and total thrombin generation as LSM increase. LSM correlated with endogenous thrombin potential, peak thrombin generation, the rate of propagation, and the rate of attenuation. This association between thrombin generation and LSM was still evident in sub-analyses excluding patients with ongoing alcohol use, active HCV infection, or a history of decompensation. In contrast, there was no significant correlation between thrombin generation, prothrombin times, Child-Pugh scores, or MELD scores. CONCLUSION: Liver stiffness measurements identify differences in parameters of thrombin generation within a cohort of compensated cirrhotic patients before changes in clotting times occur.

Transient elastography can stratify patients with Child-Pugh A cirrhosis according to risk of early decompensation.

BACKGROUND: Compensated cirrhosis has a variable prognosis depending on stage. There are currently no straightforward and robust tools in clinical practice to predict decompensation in Child-Pugh A cirrhosis. We set out to determine whether transient elastography (TE) could be used across liver disease aetiologies to determine risk of decompensation. PATIENTS AND METHODS: Participants were enrolled at two sites (Dublin and Nottingham) and followed up for a minimum of 2 years. The primary outcome of the study was liver decompensation, defined as the development of overt hepatic encephalopathy or ascites or presentation with bleeding varices. All patients received a TE examination to measure liver stiffness measurement (LSM) and had routine blood measurements taken at the baseline visit and on each subsequent visit. RESULTS: In 259 participants, the overall rate of liver-related outcome was 31 per 1000 person-years (95% confidence interval: 19-47 per 1000 person-years). Of the total population, 6 and 11% developed a liver-related outcome within 2 and 4 years of follow-up, respectively. There were no events in the population with a LSM less than 21 kPa. A LSM of more than 35 kPa was associated with a decompensation risk of 39% at 4 years. For each unit increase in the LSM above 20 kPa, the risk of liver-related outcome increased by 6% (hazard ratio=1.06; 95% confidence interval: 1.04-1.82) after adjusting for age, sex Mayo End Liver Disease Score, cohort source and aetiology. CONCLUSION: The risk of liver decompensation increased with increasing LSM in mixed aetiology compensated cirrhosis. LSM may be used to risk stratify patients, potentially reassure patients with low scores, and select patients with higher scores for experimental therapeutic studies with acceptable timelines.