Stable Cirrhotic Patients Research Articles

A modified Child-Turcotte-Pugh score based on plasma ammonia predicts survival for patients with decompensated cirrhosis.

Plasma ammonia has been shown to be an independent prognostic factor for patients with liver cirrhosis. We aimed to investigate the discrimination and calibration of a new prognostic model (aCTP) based on plasma ammonia (Amm) replacing hepatic encephalopathy (HE) in the Child-Turcotte-Pugh (CTP) score. Diagnostic test, paired design. Baseline Amm levels were corrected to the upper limit of normal (Amm-ULN). We designed the new model based on the cut-off value of Amm-ULN in the observational cohort of 554 clinically stable cirrhotic patients from January 2012 to July 2019. External validation was carried out using prospective data from 185 patients with liver cirrhosis. Our analysis showed that each 1-point increase in Amm-ULN was associated with a 2-fold increase in the likelihood of mortality [hazard ratio (HR), 2.06; 95% CI: 1.81-2.36, P < 0.001]. In the aCTP score, Amm-ULN < 1.0 was defined as a score of 1, 1.0 ≤ Amm-ULN < 1.4 as 2 and ≥1.4 as 3. The survival curves among three aCTP grades were significantly different (P < 0.0001). The aCTP score showed the better agreements between predicted and observed events in the validating cohorts than the CTP score (C-statistics: 0.75 and 0.69, P < 0.001). The aCTP score showed inspiring power to predict acute decompensation (C-statistics: 0.76; 95% CI: 0.71-0.81) and acute-on-chronic liver failure (C-statistics: 0.81; 95% CI: 0.77-0.86). This study demonstrates the feasibility and the potential for plasma Amm replacing HE (aCTP) to enhance the prognostication of transplant-free survival provided by the CTP score for patients with decompensated cirrhosis.

Protein Catabolism and the Dysregulation of Energy Intake-Related Hormones May Play a Major Role in the Worsening of Malnutrition in Hospitalized Cirrhotic Patients

Malnutrition in cirrhotic patients is extremely common and has a multifactorial aetiology, whose constitutive elements have not been completely elucidated yet. Protein depletion is particularly important and an imbalance of hormones regulating hunger and satiety may be an important additive factor. The diagnosis and treatment of malnutrition are extremely important since malnutrition is associated with higher complication rates and mortality. Our observational study aimed to study protein status and energy intake-related hormone levels in a cohort of hospitalized cirrhotic patients. We enrolled 50 hospitalized and clinically stable cirrhotic patients and assessed their nutritional status with anthropometric measurements and nitrogen balance. In a subgroup of 16 patients and 10 healthy controls, circulating ghrelin and leptin levels were studied. We observed that 60% of our patients were malnourished on the basis of the mid-arm muscle circumference values; the recorded daily protein intake was tendentially insufficient (mean protein intake of 0.7 ± 0.5 g protein/kg vs. recommended intake of 1.2–1.5 g of protein/kg/die). Cirrhotic patients had lower circulating levels of both ghrelin and leptin compared to healthy controls. In conclusion, hospitalized cirrhotic patients face a catabolic state and an imbalance in hormones regulating food intake and satiety, and these elements may play a major role in the genesis and/or the worsening of malnutrition.

Urinary free cortisol is a reliable index of adrenal cortisol production in patients with liver cirrhosis.

The measurement of total and free cortisol has been studied as a clinical index of adrenal cortisol production in patients with liver cirrhosis. Correlations between free plasma and salivary cortisol have previously been reported in stable cirrhotic patients. Urinary free cortisol constitutes an index of adrenal cortisol production; however, it has never been used in assessing adrenal function in patients with liver cirrhosis. The aim of this observational study was to determine associations between urinary free cortisol, serum total, salivary, measured and calculated plasma free cortisol levels in cirrhotics, determining which of them can be used as an indirect index of free cortisol levels. Moreover, we investigated the potential use of 24 h urinary free cortisol as a prognostic factor for mortality. Seventy-eight outpatients with liver cirrhosis were included. Serum, salivary and urinary free cortisol were measured using the electrochemiluminenscence immunoassay. Plasma free cortisol determination was conducted using a single quadrupole mass spectrometer. The quantification of free cortisol was achieved by determining the signal response on negative ESI-MS mode. Twenty-four hour urinary free cortisol levels correlated with free cortisol determined by mass spectrometer, total cortisol and calculated free cortisol levels. Patients with low levels of urinary free cortisol presented a significantly higher mortality rate compared to those with high levels. The factors associated with death risk were determined by Cox regression. In the multivariate analysis, two models were applied; in the first model, CP score, PVT and urinary free cortisol were found to be significantly related to patients' survival, whereas in the second, MELD score, ascites and urinary free cortisol were independently related to survival. This study suggests that 24 h urinary free cortisol could be considered as a potential index of adrenal cortisol production in patients with liver cirrhosis and it potentially detects patients with a high mortality risk.

Evaluation of adrenal function in hemodynamically stable patients with liver cirrhosis.

Aim of the studyTo estimate the prevalence of adrenal insufficiency (AI) in hemodynamically stable cirrhotic patients and to evaluate the potential association with patients’ clinical characteristics, cirrhosis etiology and liver disease severity.Material and methodsThe cross-sectional study included 132 stable liver cirrhosis patients. Severity of liver disease was graded using the Child-Pugh classification and Model for End-stage Liver Disease (MELD) score. The adrenal function was evaluated by measuring basal and peak cortisol after 60 minutes following the short Synacthen test (SST). Differences in terms of demographic data, clinical information and liver disease severity were compared between cirrhotic patients with and without AI.ResultsOut of 132 cirrhotic patients, 86 patients had evidence of AI based on the peak serum cortisol value while the prevalence was lower (67 patients out of 132) when basal cortisol level was taken as the basis. A total of 82 patients were classified as Child-Pugh class C, with an average MELD score of 20 ±7.1. Most patients with AI had Child-Pugh class C. Patients with AI had a higher prevalence of ascites, gastrointestinal hemorrhage, and hepatic encephalopathy, a higher MELD score and a lower serum sodium level compared to patients with normal adrenal function. AI was not related to the etiology of cirrhosis but was related to the severity of liver disease and the degree of hyponatremia.ConclusionsAdrenal insufficiency is common among hemodynamically stable patients with cirrhosis. It is related to the severity of liver disease and the degree of hyponatremia.

Frailty and reduced gait speed are independently related to mortality of cirrhotic patients in long-term follow-up

Introduction and objectivesFrailty is characterized by a poor restoration of homeostasis after a stressor event. Although it is not usually diagnosed, it has been associated with decreased survival in cirrhotic patients. We aimed to evaluate the impact of frailty and decreased gait speed over survival in cirrhotic patients at long-term follow-up. Materials and methodsWe included stable cirrhotic patients Child–Pugh B-C or MELD ≥12, ≥50 years old. We performed a clinical evaluation, anthropometry, and laboratory tests. Frailty was diagnosed using Fried Frailty Index. We evaluated survival at a 4-year follow-up. ResultsWe included 126 patients; mean age 64±8.3 years, median MELD-Na 15[12–17], median follow-up was 881 [349–1277] days. The main etiology was MAFLD (31.4%). Frailty was diagnosed in 65.1% of patients. There were no significant differences in baseline characteristics per frailty condition. Mortality was higher in frail patients than non-frail patients (68.2% versus 20.6% at 48 months, respectively; p-value <0.001). The mean gait speed in frail and non-frail patients was 0.86±0.3m/s and 1.16±0.2m/s, respectively (p-value <0.001). Interestingly, 26.9% of patients presented a reduced gait speed (≤0.8m/s). Patients with decreased gait speed also had higher mortality than patients with normal gait speed (79.9% versus 40.8%, respectively; p-value <0.001). A multivariate-adjusted model showed that decreased gait speed (HR=3.27, 95%CI:1.74–6.14; p<0.001) and frailty (HR=4.24, 95%CI:1.89–9.51; p<0.001) were associated with mortality. ConclusionsFrailty is independently associated with decreased survival at long-term follow-up. Reduced gait speed is strongly associated with mortality and could be a surrogate marker of frailty in clinical practice.

Predicting clinical decompensation in patients with cirrhosis using the Hepquant-SHUNT test.

Early identification of risk for decompensation in clinically stable cirrhotic patients helps specialists target early interventions and supports effective referrals from primary care providers to specialty centres. To examine whether the HepQuant-SHUNT test (HepQuant LLC, Greenwood Village, Colorado, USA) predicts decompensation and the need for liver transplantation, hospitalisation or liver-related death. Thirty-five compensated and 35 subjects with a previous episode of decompensation underwent the SHUNT Test and were followed for a median of 4.2years. The disease severity index (DSI) (range 0-50) was examined for association with decompensation in compensated patients; and liver transplantation, liver-related death, and the number and days of liver related hospitalisations in all. DSI prediction of decompensation was also evaluated in 84 subjects with compensated cirrhosis from the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis Trial (HALT-C) followed for a median of 5.8years. At baseline, subjects with prior decompensation had significantly higher DSI than compensated subjects (32.6 vs 20.9, P<0.001). DSI ≥24 distinguished the decompensated from the compensated patients and independently predicted adverse clinical outcomes (hazard ratio: 4.92, 95% confidence interval: 1.42-17.06). In the HALT-C cohort, 65% with baseline DSI ≥24 vs 19% with DSI <24 experienced adverse clinical outcomes (relative risk 3.45, P<0.0001). The SHUNT test is a novel, noninvasive test that predicts risk of decompensation in previously compensated patients. DSI ≥24 is independently associated with risk for clinical decompensation, liver transplantation, death and hospitalisation.

Cirrhotic Cardiomyopathy-A Veiled Threat.

Cirrhotic cardiomyopathy (CCM) is defined as cardiac dysfunction in patients with liver cirrhosis without preexisting cardiac disease. According to the definition established by the World Congress of Gasteroenterology in 2005, the diagnosis of CCM includes criteria reflecting systolic dysfunction, impaired diastolic relaxation, and electrophysiological disturbances. Because of minimal or even absent clinical symptoms and echocardiographic signs at rest according to the 2005 criteria, CCM diagnosis is often missed or delayed in most clinically stable cirrhotic patients. However, cardiac dysfunction progresses in time and contributes to the pathogenesis of hepatorenal syndrome and increased morbidity and mortality after liver transplantation, surgery, or other invasive procedures in cirrhotic patients. Therefore, a comprehensive cardiovascular assessment using newer techniques for echocardiographic evaluation of systolic and diastolic function, allowing the diagnosis of CCM in the early stage of subclinical cardiovascular dysfunction, should be included in the screening process of liver transplant candidates and patients with cirrhosis in general. The present review aims to summarize the most important pathophysiological aspects of CCM, the usefulness of contemporary cardiovascular imaging techniques and parameters in the diagnosis of CCM, the current therapeutic options, and the importance of early diagnosis of cardiovascular impairment in cirrhotic patients.

AGA Clinical Practice Update: Coagulation in Cirrhosis.

This expert review was commissioned and approved by the AGA Institute Clinical Practice Updates Committee and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership. The intent is to evaluate the current data on mechanism of altered coagulation in patients with cirrhosis, provide guidance on the use of currently available testing of the coagulation cascade, and help practitioners use anticoagulation and pro-coagulants appropriately in patients with cirrhosis. This review is framed around the best practice points, which were derived from the most impactful publications in the area of coagulation in cirrhosis and agreed to by all authors. BEST PRACTICE ADVICE 1: Global tests of clot formation, such as rotational thromboelastometry, thromboelastography, sonorheometry, and thrombin generation, may eventually have a role in the evaluation of clotting in patients with cirrhosis, but currently lack validated target levels. BEST PRACTICE ADVICE 2: In general, clinicians should not routinely correct thrombocytopenia and coagulopathy before low-risk therapeutic paracentesis, thoracentesis, and routine upper endoscopy for variceal ligation in patients with hepatic synthetic dysfunction-induced coagulation abnormalities. BEST PRACTICE ADVICE 3: Blood products should be used sparingly because they increase portal pressure and carry a risk of transfusion-associated circulatory overload, transfusion-related acute lung injury, infection transmission, alloimmunization, and/or transfusion reactions. BEST PRACTICE ADVICE 4: The following transfusion thresholds for management of active bleeding or high-risk procedures may optimize clot formation in advanced liver disease: hematocrit ≥25%, platelet count >50,000, and fibrinogen >120 mg/dL. Commonly utilized thresholds for international normalized ratio correction are not supported by evidence. BEST PRACTICE ADVICE 5: Thrombopoietin agonists are a good alternative to platelet transfusion, but require time (about 10 days) to elevate platelet levels. BEST PRACTICE ADVICE 6: The large volume of fresh frozen plasma required to reach an arbitrary international normalized ratio target, limitations of the usual target, minimal effect on thrombin generation, and adverse effects on portal pressure limit the utility of this agent significantly. BEST PRACTICE ADVICE 7: The 4-factor prothrombin complex concentrate contains both pro- and anticoagulant factors that offer an attractive low-volume therapeutic to rebalance a disturbed hemostatic system. However, dosage is, in part, based on international normalized ratio, which is problematic in cirrhosis, and published experience in liver disease is limited. BEST PRACTICE ADVICE 8: Anti-fibrinolytic therapy may be considered in patients with persistent bleeding from mucosal oozing or puncture wound bleeding consistent with impaired clot integrity. Both ε-aminocaproic acid and tranexamic acid inhibit clot dissolution. Neither is believed to generate a hypercoagulable state, although both may exacerbate pre-existing thrombi. BEST PRACTICE ADVICE 9: Desmopressin releases von Willebrand factor as its primary hemostatic mechanism. As this factor is usually elevated in cirrhosis, the agent lacks a sound evidence-based foundation, but may be useful in patients with concomitant renal failure. BEST PRACTICE ADVICE 10: Systemic heparin infusion is recommended for symptomatic deep vein thrombosis and portal and mesenteric vein thrombosis, but there are unresolved issues regarding monitoring with both the anti-Xa assay and the partial thromboplastin time due to cirrhosis-related antithrombin deficiency (heparin cofactor). BEST PRACTICE ADVICE 11: Treatment of incidental portal and mesenteric vein thrombosis depends on estimated impact on transplantation surgical complexity vs risks of bleeding and falls. Therapy with low-molecular-weight heparin, vitamin K antagonists, and direct-acting anticoagulants improve portal vein repermeation vs observation alone. BEST PRACTICE ADVICE 12: Direct-acting anticoagulants, such as the factor Xa and thrombin inhibitors, are relatively safe and effective in stable cirrhotic patients, but are in need of further study in patients with more advanced liver disease.

Un-precipitated acute kidney injury is uncommon among stable patients with cirrhosis and ascites.

Acute episodes of renal dysfunction or acute kidney injury (AKI) in cirrhotic patients with ascites are mostly precipitated by an acute event. The prevalence of un-precipitated AKI in stable ascitic cirrhotic patients is unknown. The aims of this study were to determine (i) the prevalence of un-precipitated AKI in stable cirrhotics with ascites and (ii) any predictive factors for its development. A total of 1115 stable cirrhotic patients with mild liver and renal dysfunction but varying degrees of ascites severity from 3 previous satavaptan vs placebo randomized controlled trials (Group A, ascites requiring diuretics but not paracentesis; Group B, ascites requiring frequent paracentesis; Group C, refractory ascites) were included. AKI was diagnosed when there was either an increase of ≥0.3mg/dL in ≤48hours or a 50% increase in serum creatinine, and staged according to the fold increase of the serum creatinine. Two serum creatinine levels measured maximally 7days apart at screening and at randomization of the satavaptan studies with no acute intervening events were used. The prevalence of un-precipitated AKI was 1.8% overall, with the prevalence rising with increasing severity of ascites. Ninety-five per cent of cases were stage 1, with 15% progression rate, 3 reaching the severity of type 1 acute hepatorenal syndrome. Ascites severity was the most powerful predictor for un-precipitated AKI development, which did not predict overall mortality. Increased prevalence of AKI with more severe ascites despite minimal baseline liver and renal dysfunction suggests that frequent monitoring of renal function in these patients is mandatory.

Circulating levels of pentraxin-3 (PTX3) in patients with liver cirrhosis

BackgroundDespite the circulating levels of PTX3 were related to the severity of various diseases, there are no studies investigating its role in patients with liver cirrhosis. We aimed to study PTX3 levels in patients with liver cirrhosis. Material and methodsA prospective cohort study included 130 patients hospitalized for acute decompensation of liver cirrhosis, 29 stable cirrhotic outpatients and 32 healthy controls evaluated in a tertiary hospital in Southern Brasil. ResultsThe median PTX3 level was significantly higher in stable cirrhotic patients compared to controls (2.6 vs. 1.1 ng/mL; p < 0.001), hospitalized cirrhotic patients compared to controls (3.8 vs. 1.1 ng/mL; p < 0.001), and hospitalized cirrhotic patients compared to stable cirrhotic patients (3.8 vs. 2.6 ng/ mL; p = 0.001). A positive correlation was found between PTX3 and serum creatinine (r = 0.220; p = 0.012), Chronic Liver Failure -Sequential Organ Failure Assessment score (CLIF-SOFA) (r = 0.220; p = 0.010), MELD (r = 0.279; p = 0.001) and Child-Pugh score (r = 0.224; p = 0.010). Significantly higher levels of PTX3 were observed in patients on admission with ACLF (8.9 vs. 3.1 ng/mL; p < 0.001) and MELD score ≥ 20 (6.6 vs. 3.4 ng/mL; p = 0.002). Death within 90 days occurred in 30.8% of patients and was associated with higher levels of PTX3 (5.3 vs. 3.4 ng/mL; p = 0.009). The probability of Kaplan-Meier survival was 77.0% in patients with PTX-3 < 5.3 ng mL (upper tercile) and 53.5% in those with PTX3 ≥ 5.3 ng/mL (p = 0.002). ConclusionThese results indicate the potential for use of PTX3 as an inflammatory biomarker for the prognosis of patients with hepatic cirrhosis.

Balanced haemostasis with both hypo- and hyper-coagulable features in critically ill patients with acute-on-chronic-liver failure

BackgroundCirrhotic patients have complex haemostatic abnormalities. Current evidence suggests stable cirrhotic (SC) patients have a “re-balanced” haemostatic state. However, limited data exists in acute decompensated (AD) or acute on chronic liver failure (ACLF) patients. MethodsWe utilised thrombin generation analysis, fibrinolysis assessment, and evaluation of haemostatic parameters to assess haemostasis in liver disease of progressive severity. ResultsThe study cohorts were comprised of: SC, n=8; AD n=44; ACLF, n=17; and Healthy Control (HC), n=35. There was a progressive increase across the cohorts in INR (p=0.0001), Factor VIII (p=0.0001) and VWF levels (p=0.0001) and a correspondingly decrease in anti-thrombin (p=0.0001), ADAMTS-13 (p=0.01) and fibrinogen levels (p=0.0001). In the presence of thrombomodulin, thrombin generation was equivalent or significantly higher in all the cohorts compared to HC (p=0.0001). Compared to AD, ACLF had a lower ETP (p=0.002) and thrombin peak (p=0.0001). There was no significant difference across the cohorts in clot lysis time (p=0.07), although compared to HC, AD had a significantly shorter lysis time (p=0.001). ConclusionsOur cohorts, despite significant differences in haemostatic parameters, displayed intact thrombin generation but progressive hypo-functional clot stability and potentially but not universal hyper-functional haemostasis.

Bleeding Risk with Invasive Procedures in Patients with Cirrhosis and Coagulopathy.

Previous perceptions of cirrhosis as a hypocoagulable state have resulted in empirical blood product transfusions prior to invasive procedures. We evaluate procedure-related bleeding risks in patients with cirrhosis, assess the utility of conventional and newer global coagulation tests, and explore evidence surrounding prophylactic transfusion strategies. Recent literature supports the concept of a rebalanced, albeit fragile, haemostasis equilibrium in cirrhosis, with a potential hypercoagulable tendency in stable patients. Standard coagulation tests provide a poor reflection of bleeding risks and yet are relied upon for transfusion thresholds. Consequently, a sizeable proportion of patients receive unnecessary blood products. The role of viscoelastic tests to guide transfusions requires further evaluation. In stable cirrhotic patients, procedure-related bleeding rates appear low. Prophylactic transfusion strategies based on arbitrary thresholds lack evidence of clinical benefit. There is a pressing need for point-of-care coagulation tests that represent the complex coagulopathy of cirrhosis and well-powered randomised controlled trials to develop evidence-based pre-procedure transfusion guidelines.

Evaluation of Adrenal Function in Nonhospitalized Patients with Cirrhosis.

Background Patients with cirrhosis and advancing hepatic insufficiency may show various degrees of other organ malfunction, including brain, kidney, and lung. Several studies have also shown a high prevalence of adrenal insufficiency in cirrhotic patients that may cause hemodynamic instability. Materials and Methods In this study we prospectively evaluated adrenal function in a population of nonhospitalized cirrhotic patients. Categorization of liver disease severity was done according to model for end-stage liver disease (MELD) score. Adrenocorticotropic hormone stimulation testing was performed on subjects using 250 μg of synthetic short acting hormone; radio immunoassay was used to measure plasma cortisol levels. Results Of 105 cirrhotic patients, 15.23% had evidence of adrenal insufficiency. These patients were not statistically different from those with normal adrenal function in levels of serum creatinine or bilirubin, MELD score, or presence of cirrhosis related complications. Significant differences were seen in mean international normalized ratio and serum sodium. Patients with a sodium level < 135 mEq/L had a higher rate (31.25%) of adrenal insufficiency. Conclusion Adrenal dysfunction was identified in a population of stable nonhospitalized cirrhotic patients. Our results suggest a possible role for adrenal dysfunction as a contributing factor in hyponatremia in cirrhosis independent of other known factors of neurohormonal activation secondary to systemic vasodilation.

Modification in CSF specific gravity in acutely decompensated cirrhosis and acute on chronic liver failure independent of encephalopathy, evidences for an early blood-CSF barrier dysfunction in cirrhosis.

Although hepatic encephalopathy (HE) on the background of acute on chronic liver failure (ACLF) is associated with high mortality rates, it is unknown whether this is due to increased blood-brain barrier permeability. Specific gravity of cerebrospinal fluid measured by CT is able to estimate blood-cerebrospinal fluid-barrier permeability. This study aimed to assess cerebrospinal fluid specific gravity in acutely decompensated cirrhosis and to compare it in patients with or without ACLF and with or without hepatic encephalopathy. We identified all the patients admitted for acute decompensation of cirrhosis who underwent a brain CT-scan. Those patients could present acute decompensation with or without ACLF. The presence of hepatic encephalopathy was noted. They were compared to a group of stable cirrhotic patients and healthy controls. Quantitative brain CT analysis used the Brainview software that gives the weight, the volume and the specific gravity of each determined brain regions. Results are given as median and interquartile ranges and as relative variation compared to the control/baseline group. 36 patients presented an acute decompensation of cirrhosis. Among them, 25 presented with ACLF and 11 without ACLF; 20 presented with hepatic encephalopathy grade≥2. They were compared to 31 stable cirrhosis patients and 61 healthy controls. Cirrhotic patients had increased cerebrospinal fluid specific gravity (CSF-SG) compared to healthy controls (+0.4%, p<0.0001). Cirrhotic patients with ACLF have decreased CSF-SG as compared to cirrhotic patients without ACLF (-0.2%, p=0.0030) that remained higher than in healthy controls. The presence of hepatic encephalopathy did not modify CSF-SG (-0.09%, p=0.1757). Specific gravity did not differ between different brain regions according to the presence or absence of either ACLF or HE. In patients with acute decompensation of cirrhosis, and those with ACLF, CSF specific gravity is modified compared to both stable cirrhotic patients and healthy controls. This pattern is observed even in the absence of hepatic encephalopathy suggesting that blood-CSF barrier impairment is manifest even in absence of overt hepatic encephalopathy.

The importance of salivary cortisol in the diagnosis of adrenal insufficiency in cirrhosis.

Reports on adrenal insufficiency (AI) are unexpectedly high in cirrhosis, and the diagnosis of this condition remains a challenge. We aimed to define the prevalence rate of AI in stable cirrhotic patients and determine the correlations of free cortisol and salivary cortisol with total cortisol. Between January 2011 and September 2011, 110 consecutive cirrhotic patients without any infection or hemodynamic instability were enrolled. Baseline total and salivary cortisol levels were measured. The free cortisol level was calculated according to the Coolens' formula. Post-stimulation total and salivary cortisol levels were measured, and the free cortisol level was recalculated. The mean age of the patients was 62.1±11.4 years. There were 54 males (49.1%). The mean Child-Turcotte-Pugh (CTP) score was 7.2±2.3. Twenty-two (20%) patients were at the CTP-C level. AI was present in 23 (20.9%) and 17 (15.5%) of all patients according to the total and free cortisol criteria, respectively. For basal and stimulated levels, salivary cortisol rather than total cortisol correlates well with free cortisol. The diagnosis of AI on the basis of total cortisol measurement overestimates the prevalence of AI in cirrhosis. Salivary cortisol, which correlates well with free cortisol, is a promising alternative for the diagnosis of AI in cirrhotic patients.

Abstract 433: Liver Disease Alters HDL Metabolism and Function

Background/Aims: High-density lipoproteins (HDLs) are important endogenous inhibitors of inflammatory responses. Dysfunctional HDL might contribute to the serious complications experienced by patients with acute and chronic liver failure, but the effect of cirrhosis on several metrics of HDL function is not understood. Methods: We measured metrics of HDL function in an explorative cross sectional study of 59 patients with compensated cirrhosis, 21 patients with acutely decompensated cirrhosis and 20 healthy controls. HDL particle size was assessed using native gel electrophoresis. HDL cholesterol efflux potential was assessed using [ 3 H]-cholesterol labeled macrophages. Paraoxonase activity was determined by photometry using phenylacetate as substrate. Nuclear factor-κB activation in monocytes and cytokines were assessed by flow cytometry. Endothelial regenerative activity was determined using an electric cell-substrate impedance sensing system. Results: Sera of cirrhotic patients showed low HDL-cholesterol levels and profoundly suppressed activities of several serum enzymes involved in HDL maturation and metabolism. Native gel electrophoresis analyses revealed that cirrhotic HDL shifts toward the larger HDL 2 subclass. We observed that (i) HDL cholesterol efflux capability, (ii) paraoxonase activity, (iii) the ability to inhibit monocyte production of pro-inflammatory cytokines and (iv) endothelial regenerative activities were significantly reduced in stable cirrhotic patients, and markedly suppressed in acutely decompensated patients. Of particular interest, HDL cholesterol efflux capacity appeared to be strongly associated with mortality of cirrhotic patients, independently of HDL cholesterol levels. Conclusion: Cirrhosis affects HDL metabolism and several metrics of HDL function. HDL cholesterol efflux capacity appears to predict 1-year mortality independent of HDL-cholesterol levels.

ASSESSMENT OF ADRENOCORTICAL DYSFUNCTION IN PATIENTS WITH STABLE LIVER CIRRHOSIS.

Relative adrenal insufficiency (RAI) is common in the setting of critical illness as well as in hemodynamically instable cirrhotic patients with sepsis. Several studies have also shown that RAI is frequent in patients with stable cirrhosis without sepsis. The aim of this study was to prospectively assess the incidence of RAI in patients with stable cirrhosis. Forty-seven patients with hemodynamically stable liver cirrhosis without sepsis were prospectively included. RAI, assessed by using low dose-short Synacthen test (LD-SST), was defined as either a basal total cortisol concentration below 3.6 µg/dL or a peak total serum cortisol ≤ 16 µg/dL at 30 min after stimulation. RAI was present in 10 (21.3%) of 47 cirrhotic patients. Peak cortisol level was negatively correlated with the severity of cirrhosis evaluated by Child-Turcotte-Pugh (CTP) (r=-0.46; P=0.001) and Model for End-Stage Liver Disease (MELD) (r=-0.51; P=0.001) scores. The frequency of RAI increased from CTP-A (10%) to CTP-B (30%) to CTP-C (60%). RAI diagnosed by LD-SST is frequent in patients with stable cirrhosis and is related to the severity of liver disease. Further studies are needed to define clinical importance of RAI in stable cirrhotic patients.

Immune dysfunction in cirrhosis: Distinct cytokines phenotypes according to cirrhosis severity

Background/objectivesCirrhosis associated immune dysfunction has been proposed to switch from a pro-inflammatory phenotype in stable cirrhosis to an immunodeficient one in patients with decompensated cirrhosis and acute-on-chronic liver failure. The aim of the present study was to compare serum cytokine levels between healthy patients, stable cirrhosis, and decompensated cirrhotic patients with and without development of acute-on-chronic liver failure (ACLF); and to explore whether any of the measured cytokines is associated with cirrhosis severity and prognosis in ACLF patients. MethodsPatients were enrolled from October 2013 to May 2014 in two hospitals located in Buenos Aires. Cirrhotic patients with an acute decompensating event were enrolled accordingly to the development of ACLF defined by the CANONIC study group. There were two control groups: healthy subjects (n=14) and stable cirrhotic patients (n=14). Demographic, clinical and biochemical data were obtained. Seventeen cytokines were measured using Bio-Plex Pro Human Cytokine 17-plex Assay. ResultsOf the 49 decompensated cirrhotic patients enrolled, 18 (36.7%) developed ACLF. Leukocyte count, MELD score at admission, Clif-SOFA at admission and day 7 were significantly higher in the ACLF group (p=0.046, p<0.001, p<0.001, p<0.001 respectively) as well as short-term mortality (p<0.001) compared to stable and decompensated cirrhotic patients. In comparison with healthy controls, stable cirrhotic and decompensated cirrhotic patients showed increased levels of pro-inflammatory and anti-inflammatory cytokines: IL-6, IL-7, IL-8, IL-10, IL 12, and TNF-α. Decompensated cirrhotic patients with the development of ACLF showed a significant decrease of IL-7, IL-10, IL-12, TNF-α, MCP-1 and IFN-γ, but a sustained response of IL-6 and IL-8. When evaluating cirrhosis severity, IL-6 and IL-8 correlated positively with MELD score, whereas only IL-6 correlated positively with Clif-SOFA score at day 7; IL-2 correlated negatively with Clif-SOFA at admission. In comparison with all scores, leukocyte count showed positive correlation and IFN-γ negative correlation with disease severity. When evaluating survival, only MELD and Clif-SOFA scores had a significant association with mortality. ConclusionsPro-inflammatory cytokines and chemo-attractant elements are increased in cirrhosis in comparison with healthy subjects, and display higher values concomitantly with cirrhosis progression. However, in acute-on-chronic liver failure an opposite cytokine pattern that can be resumed as a combination of immune paresis and excessive inflammatory response was observed. Several pro-inflammatory cytokines (IL-2, IL-6, IL-8 and IFN-γ) showed correlation with disease severity; their utility as prognostic biomarkers needs to be further studied.

Hepatitis C virus and liver transplantation: where do we stand?

The hepatitis C virus (HCV) infects more than 180 million people globally, with increasing incidence, especially in developing countries. HCV infection frequently progresses to liver cirrhosis leading to liver transplantation or death, and HCV recurrence still constitutes a major challenge for the transplant team. Antiviral therapy is the only available instrument to slow down this process, although its actual impact on liver histology, in responders and nonresponders, is still controversial. We are now facing a "new era" of direct antiviral agents that is already changing the approach to HCV burden both in the pre- and in the post-liver transplantation settings. Available data on sofosbuvir/ledipasvir and sofosbuvir/simeprevir in patients with decompensated cirrhosis sustain a SVR12 of 89% , but one-third of patients do not clinically improved. The sofosbuvir/ribavirin treatment in stable cirrhotic patients with HCC before liver transplantation is associated with 2% recurrence rate if liver transplantation is performed at least one month after undetectable HCV-RNA is achieved. The treatment of recurrence with the new antiviral drugs is associated with a SVR that ranges between 60 and 90%. In this review, we have focused on the evolution of antiviral therapy for HCV recurrence from the "old" interferon-based therapy to the "new" interferon-free regimens, highlighting useful information to aid the transplant hepatologist in the clinical practice.

PWE-098 Increase in gut permeability is an early event in cirrhosis and is not associated with bacterial translocation, systemic inflammation or clinical features: a prospective longitudinal study

Introduction In cirrhosis, bacterial translocation (BT) is an early event and predicts occurrence of complications such as infection and mortality. In advanced liver failure, this is associated with increased gut permeability (GP) but the data in well-compensated cirrhosis is lacking. The aim of this study was to determine whether (a) GP is altered in patients with well-compensated cirrhosis (b) this was associated with bacterial translocation and (c) complications of cirrhosis. Method Fifty-two stable cirrhotic patients (male: 33; age: 57, 1 ± 8, 36; Child A: 84, 6%, Child B: 15, 4%) were included and studied longitudinally at the time of inclusion and 1-month afterwards. Clinical and biochemical variables and complications were recorded. GP was measured using standard sugar probe-based assays. Bacterial DNA was measured in serum samples by PCR reaction for the 16S ribosomal RNA gene. Results 19 patients (36, 5%) had an abnormal GP (>0,033). There are no differences in gender, age, aetiology; diabetes, WCC, MELD (9, 0 ± 2, 7 vs 9, 4 ± 3, 5) and complications of cirrhosis (infection: 18, 2% vs 10.5%, ascites: 54, 5% vs 31, 6%; HE 15, 2% 10, 5% and varices: 42, 4% vs 52, 6%). Only 2 patients showed evidence of BT. At 1-month, in patients with a GP <0,033, 69% showed an increase, 7 (24, 1%) a decrease and 2 were unchanged in the GP rate. In patients with abnormal GP, it worsened in 31, 3% and in 68, 7% it improved. The two patients that showed evidence of BT became negative after one month and both of them displayed an improvement of their GP. 3-patients became positive after 1-month, with two showing worsening of GP. Conversely, all of these changes were not associated with any complications of cirrhosis. Conclusion The data of this prospective longitudinal study shows that alteration in GP occurs in a third of wellcompensated cirrhosis and is a dynamic abnormalities that improves or worsens with no apparent clinical sequaela. Increased GP is not associated with evidence of bacterial translocation, clinical characteristics or systemic inflammation in well-compensated cirrhosis. It is likely that increased gut permeability is an early event but bacterial translocation in humans occurs late and factors other than translocated bacteria such as its products or metabolites contribute to clinical manifestations. Disclosure of interest None Declared.