Cumulative incidence of solid and hematological De novo malignancy after liver transplantation in a multicentre cohort.

BACKGROUND: Recent innovations in the field of liver transplantation have led to a wealth of new treatment regimes, with potential impact on the onset of de novo malignancies (DNM). The aim of this multicenter cohort study was to provide contemporary figures for the cumulative incidences of solid and hematological DNM after liver transplantation. METHODS: We designed a retrospective cohort study including patients undergoing LT between 2000 and 2015 in three Italian transplant centers. Cumulative incidence was calculated by Kaplan-Meyer analysis. RESULTS: The study included 789 LT patients with a median follow-up of 81 months (IQR: 38-124). The cumulative incidence of non-cutaneous DNM was 6.2% at 5-years, 11.6% at 10-years and 16.3% at 15-years. Post-Transplant Lymphoproliferative Disorders (PTLD) were demonstrated to have a cumulative incidence of 1.0% at 5-years, 1.6% at 10-years and 2.2% at 15-years. Solid Organ Tumors (SOT) demonstrated higher cumulative incidences - 5.3% at 5-years, 10.3% at 10-years and 14.4% at 15-years. The most frequently observed classifications of SOT were lung (rate 1.0% at 5-years, 2.5% at 10-years) and head & neck tumors (rate 1.3% at 5-years, 1.9% at 10-years). CONCLUSIONS: Lung tumors and head & neck tumors are the most frequently observed SOT after LT.

Low-grade endotoxemia and platelet activation in cirrhosis.

Patients with cirrhosis may display impaired or enhanced platelet activation, but the reasons for these equivocal findings are unclear. We investigated if bacterial lipopolysaccharide (LPS) is implicated in platelet activation. In a cross-sectional study, conducted in an ambulatory care clinic and hospital, comparing 69 cirrhosis patients and 30 controls matched for sex, age, and atherosclerotic risk factors, serum levels of LPS, soluble cluster of differentiation 40 ligand and p-selectin (two markers of platelet activation), and zonulin (a marker of gut permeability) were investigated. Ex vivo and in vitro studies were also performed to explore the effect of LPS on platelet activation. Compared to controls, cirrhosis patients displayed higher serum levels of LPS (6.0 [4.0-17.5] versus 57.4 [43.4-87.2] pg/mL, P < 0.0001), soluble cluster of differentiation 40 ligand (7.0 ± 2.2 versus 24.4 ± 13.3 ng/mL, P < 0.0001), soluble p-selectin (14.2 ± 4.05 versus 33.2 ± 15.2 ng/mL, P < 0.0001), and zonulin (1.87 ± 0.84 versus 2.54 ± 0.94 ng/mL, P < 0.006). LPS significantly correlated with zonulin (r = 0.45, P < 0.001). Ex vivo studies showed that platelets from cirrhosis patients were more responsive to the agonists independently from platelet count; this phenomenon was blunted by incubation with an inhibitor of Toll-like receptor 4. In vitro study by normal platelets showed that LPS alone (50-150 pg/mL) did not stimulate platelets but amplified platelet response to the agonists; Toll-like receptor 4 inhibitor blunted this effect. CONCLUSION: LPS may be responsible for platelet activation and potentially contributes to thrombotic complications occurring in cirrhosis. (Hepatology 2017;65:571-581).

A low muscle mass increases mortality in compensated cirrhotic patients with sepsis.

BACKGROUND & AIMS: Severe infections and muscle wasting are both associated to poor outcome in cirrhosis. A possible synergic effect of these two entities in cirrhotic patients has not been previously investigated. We aimed at analysing if a low muscle mass may deteriorate the outcome of cirrhotic patients with sepsis. METHODS: Consecutive cirrhotic patients hospitalized for sepsis were enrolled in the study. Patients were classified for the severity of liver impairment (Child-Pugh class) and for the presence of "low muscle mass" (mid-arm muscle circumference<5th percentile). The development of complication during hospitalization and survival was analysed. RESULTS: There were 74 consecutive cirrhotics with sepsis. Forty-three of these patients showed low muscle mass. In patients with and without low muscle mass, severity of liver disease and characteristics of infections were similar. Mortality tended to be higher in patients with low muscle mass (47% vs 26%, P = .06). A multivariate analysis selected low muscle mass (P < .01, HR: 3.2, IC: 1.4-4.8) and Child-Pugh C (P < .01, HR: 3.3, 95% IC: 1.5-4.9) as independent predictors of in-hospital mortality. In Child-Pugh A-B patients, mortality was higher in patients with low muscle mass compared with those without (50% vs 16%; P = .01). The mortality rate and the incidence of complications in malnourished patients classified in Child-Pugh A-B were similar to those Child-Pugh C. CONCLUSIONS: Low muscle mass worsen prognosis in cirrhotic patients with severe infections. This is particularly evident in patients with Child A-B cirrhosis in whom the coexistence of low muscle mass and sepsis caused a negative impact on mortality similar to that observable in all Child C patients with sepsis.

An empirical broad spectrum antibiotic therapy in health-care-associated infections improves survival in patients with cirrhosis: A randomized trial.

UNLABELLED: Early diagnosis and appropriate treatment of infections in cirrhosis are crucial because of their high morbidity and mortality. Multidrug-resistant (MDR) infections are on the increase in health care settings. Health-care-associated (HCA) infections are still frequently treated as community-acquired with a detrimental effect on survival. We aimed to prospectively evaluate in a randomized trial the effectiveness of a broad spectrum antibiotic treatment in patients with cirrhosis with HCA infections. Consecutive patients with cirrhosis hospitalized with HCA infections were enrolled. After culture sampling, patients were promptly randomized to receive a standard or a broad spectrum antibiotic treatment (NCT01820026). The primary endpoint was in-hospital mortality. Efficacy, side effects, and the length of hospitalization were considered. Treatment failure was followed by a change in antibiotic therapy. Ninety-six patients were randomized and 94 were included. The two groups were similar for demographic, clinical, and microbiological characteristics. The prevalence of MDR pathogens was 40% in the standard versus 46% in the broad spectrum group. In-hospital mortality showed a substantial reduction in the broad spectrum versus standard group (6% vs. 25%; P = 0.01). In a post-hoc analysis, reduction of mortality was more evident in patients with sepsis. The broad spectrum showed a lower rate of treatment failure than the standard therapy (18% vs. 51%; P = 0.001). Length of hospitalization was shorter in the broad spectrum (12.3 ± 7 days) versus standard group (18 ± 15 days; P = 0.03). Five patients in each group developed a second infection during hospitalization with a similar prevalence of MDR (50% broad spectrum vs. 60% standard). CONCLUSIONS: A broad spectrum antibiotic therapy as empirical treatment in HCA infections improves survival in cirrhosis. This treatment was significantly effective, safe, and cost saving.

Hepatic encephalopathy expands the predictivity of model for end-stage liver disease in liver transplant setting: Evidence by means of 2 independent cohorts.

Despite its documented prognostic relevance, hepatic encephalopathy (HE) is not considered in liver transplantation (LT) due to its possible poor objectivity. To override this problem, we aimed to analyze if an objective diagnosis of HE may confer additional mortality risk beyond MELD. Study and validation cohorts of patients with cirrhosis were considered in Italy and Canada, respectively. Patients were considered to be HE+ if an episode of overt HE was documented in a hospitalization. Of the 486 patients enrolled in Italy, 184 (38%) were HE+. During the 6-month follow-up, 77 patients died and 50 underwent transplantation. The 6-month mortality of HE+ versus HE- patients was significantly higher (P < 0.001). Model for End-Stage Liver Disease (MELD; subdistribution hazard ratio [sHR], 1.2; 95% confidence interval [CI], 1.1-1.2; P < 0.001), HE+ (sHR, 3.6; 95% CI, 1.8-7.1; P < 0.001), and sodium (sHR, 0.9; 95% CI, 0.8-0.9; P < 0.001) were independent predictors of 6-month mortality. In HE+ patients, short-term mortality increased across the entire MELD spectrum (range, 6-40). The results were unchanged by including or excluding patients with hepatocellular carcinoma or stratifying patients according to HE characteristics. The higher 6-month mortality of HE+ versus HE- patients was confirmed also in the Canadian cohort (P < 0.001; n = 300, 33% HE+; 33 died, 104 transplanted). A similar and statistically significant C-index increase derived by the incorporation of HE in MELD was observed both in the Italian (from 0.67 to 0.75) and Canadian (from 0.69 to 0.74) cohorts. A score based on MELD plus 7 points (95% CI, 4-10) for HE+ patients optimally predicted 6-month mortality in the 2 cohorts. According to the net reclassification index, by not considering HE, 29% of overall patients were misclassified by MELD score. In conclusion, the incorporation of HE in MELD score might improve the listing and allocation policy in LT. Liver Transplantation 22 1333-1342 2016 AASLD.

The chronic use of beta-blockers and proton pump inhibitors may affect the rate of bacterial infections in cirrhosis.

BACKGROUND & AIMS: Bacterial infections are among the most common and life-threatening complications in cirrhosis. Qualitative and quantitative modifications of the gut microbiota, dysfunction of the intestinal barrier and multiple immune defects are factors that contribute to a pathological 'bacterial translocation' (BT), leading to a higher susceptibility to infections in cirrhotic patients. Long-term therapies, commonly adopted in cirrhotic patients, may influence BT and modify the risk of infection in these patients. To investigate the influence of chronic therapies on the prevalence and microbiological characteristics of infections in cirrhosis. METHODS: Consecutive cirrhotic patients hospitalised from 2008 to 2013 were enrolled. All previous treatments were carefully recorded. Infections were actively sought out, patients were actively monitored for infection, and possible risk factors were evaluated. RESULTS: Four hundred cirrhotic patients were included. The most frequent therapies were proton pump inhibitors (PPIs) (67%), non-absorbable-disaccharides (44%), beta-blockers (BBs) (39%) and non-absorbable-antibiotics (10%). Child-Pugh C (P < 0.001; OR 5; 95%CI: 2.6-9.9) and PPI therapy (P = 0.008; OR 2; 95% CI: 1.2-3.2) were found to be independent predictors of infection, and the use of BBs was a protective factor (P = 0.001; OR 0.46; 95%CI: 0.3-0.7). Cirrhotic patients with bacterial infection showed lower morbidity and mortality when taking BBs. CONCLUSIONS: Proton pump inhibitors increase the risk of infection in cirrhosis and should not be prescribed in these patients without specific indications. In contrast, the use of BBs is associated with a lower rate of infection and attenuates the consequences of infections in cirrhotic patients.

Increased risk of cognitive impairment in cirrhotic patients with bacterial infections.

BACKGROUND & AIMS: A causal relationship between infection, systemic inflammation, and hepatic encephalopathy (HE) has been suggested in cirrhosis. No study, however, has specifically examined, in cirrhotic patients with infection, the complete pattern of clinical and subclinical cognitive alterations and its reversibility after resolution. Our investigation was aimed at describing the characteristics of cognitive impairment in hospitalized cirrhotic patients, in comparison with patients without liver disease, with and without infection. METHODS: One hundred and fifty cirrhotic patients were prospectively enrolled. Eighty-one patients without liver disease constituted the control group. Bacterial infections and sepsis were actively searched in all patients independently of their clinical evidence at entry. Neurological and psychometric assessment was performed at admission and in case of nosocomial infection. The patients were re-evaluated after the resolution of the infection and 3months later. RESULTS: Cognitive impairment (overt or subclinical) was recorded in 42% of cirrhotics without infection, in 79% with infection without SIRS and in 90% with sepsis. The impairment was only subclinical in controls and occurred only in patients with sepsis (42%). Multivariate analysis selected infection as the only independent predictor of cognitive impairment (OR 9.5; 95% CI 3.5-26.2; p=0.00001) in cirrhosis. The subclinical alterations detected by psychometric tests were also strongly related to the infectious episode and reversible after its resolution. CONCLUSIONS: Infections are associated with a worse cognitive impairment in cirrhotics compared to patients without liver disease. The search and treatment of infections are crucial to ameliorate both clinical and subclinical cognitive impairment of cirrhotic patients.

Muscle depletion increases the risk of overt and minimal hepatic encephalopathy: results of a prospective study.

Muscle depletion is frequently encountered in cirrhotic patients. As muscle may represents an alternative site of ammonia detoxification in liver diseases, our study was aimed at investigating whether a decrease in muscle mass or function may independently influence the prevalence of neurocognitive alterations in cirrhosis. Three-hundred consecutive hospitalized cirrhotic patients were prospectively enrolled. Liver function, a complete neurocognitive assessment for the diagnosis of clinical or subclinical hepatic encephalopathy (HE) and parameters of nutritional status and muscle function were evaluated in each patient at admission. Clinically overt HE, at admission or in the last 12 months, or a diagnosis of minimal HE were significantly higher in cirrhotic patients with muscle depletion or decreased muscle strength. The fasting venous blood ammonia concentrations were also higher in this group. Muscle depletion was an independent risk factor at multivariate analysis both for overt and minimal HE. In conclusion cirrhotic patients with muscle depletion are at higher risk of HE and the amelioration of nutritional status is a possible goal to decrease the prevalence of neurocognitive alterations in these patients.

Impact of COVID-19 Pandemic on Colorectal Cancer Screening Program.

INTRODUCTION: One of the main clusters of coronavirus disease-2019 (COVID-19) has been identified in Italy. Following European and local guidelines, Italian endoscopy units modulated their activity. We aimed at analyzing the need and safety to continue selective colorectal cancer screening (CRCS) colonoscopies during the COVID-19 pandemic. PATIENTS AND METHODS: We carried out a retrospective controlled cohort study in our "COVID-free" hospital to compare data of the CRCS colonoscopies of the lockdown period (March 9 to May 4, 2020) with those of the same period of 2019 (control group). A pre/post endoscopic sanitary surveillance for COVID-19 infection was organized for patients and sanitary staff. RESULTS: In the lockdown group, 60 of 137 invited patients underwent endoscopy, whereas in the control group, 238 CRCS colonoscopies (3.9-fold) were performed. In the lower number of examinations during the lockdown, we found more colorectal cancers (5 cases; 8% vs. 3 cases; 1%; P = .002). The "high-risk" adenomas detection rate was also significantly higher in the "lockdown group" than in controls (47% vs. 25%; P = .001). A multiple regression analysis selected relevant symptoms (hazard ratio [HR], 3.1), familiarity (HR, 1.99), and lockdown period (HR, 2.2) as independent predictors of high-risk lesions (high-risk adenomas and colorectal cancer). No COVID-19 infections were reported among staff and patients. CONCLUSIONS: The overall adherence to CRCS decreased during the pandemic, but the continuation of CRCS colonoscopies was efficacious and safe.

Cirrhotic patients are at risk for health care-associated bacterial infections.

BACKGROUND & AIMS: Bacterial infections are a frequent and serious burden among patients with cirrhosis because they can further deteriorate liver function. We assessed the epidemiology, risk factors, and clinical consequences of bacterial infections in hospitalized cirrhotic patients. METHODS: In a cohort of hospitalized cirrhotic patients (n = 150) referred to a tertiary care setting, all episodes of bacterial infections were recorded prospectively. Infections were classified as community-acquired (CA), health care-associated (HCA), or hospital-acquired (HA). Site of infection, characteristics of bacteria, and prevalence of antibiotic resistance were reported; consequences for liver function and patient survival were evaluated. RESULTS: Fifty-four infections were observed among 50 patients (12 CA, 22 HCA, and 20 HA). Bacterial resistance was more frequent among patients with HCA or HA infections (64% of isolates). Mortality was 37% from HA, 36% from HCA, and 0% from CA infections. Independent predictors of infection included a previous infection within the past 12 months (P = .0001; 95% confidence interval [CI], 2.2-10.6), model of end-stage liver disease score ≥ 5 (P = .01; 95% CI, 1.3-6.1), and protein malnutrition (P = .04; 95% CI, 1.5-10). Infectious episodes worsened liver function in 62% of patients. Patients with infection more frequently developed ascites, hepatic encephalopathy, hyponatremia, hepatorenal syndrome, or septic shock. Child class C (P = .006; 95% CI, 1.67-23.7), sepsis (P = .005; 95% CI, 1.7-21.4), and protein malnutrition (P = .001; 95% CI, 2.8-38.5) increased mortality among patients in the hospital. CONCLUSIONS: In hospitalized cirrhotic patients, the most frequent infections are HCA and HA; these infections are frequently resistant to antibiotics. As infections worsen, liver function deteriorates and mortality increases. Cirrhotic patients should be monitored closely for infections.

The additive value of sarcopenia, myosteatosis and hepatic encephalopathy in the predictivity of model for end-stage liver disease.

BACKGROUND: Since the use of the Model for End-Stage Liver Disease (MELD) score for establishing the prognosis of cirrhotic patients has been introduced, questions have been raised whether complications of liver cirrhosis would provide additional information. Myosteatosis, sarcopenia and hepatic encephalopathy (HE) are frequent in cirrhosis and may affect prognosis. Aim of the study was analyzing if these factors are independently related to survival and may improve the accuracy of MELD. METHODS: 249 cirrhotics that underwent abdominal CT-scan were enrolled. For each patient, information about previous episodes of HE and muscle alterations were obtained. Patients were followed until transplantation or death. RESULTS: History of HE, MELD, sarcopenia and myosteatosis were independently associated with mortality. The MELD-Sarco-Myo-HE score added accuracy to the MELD score alone for 6- and 3-months mortality. By removing HE, as the only not quantifiable parameter of the model, no relevant decrease in accuracy for 6- and 3-months mortality detection was observed. CONCLUSIONS: The accuracy of MELD in predicting 3- and 6-months mortality may be improved by considering the muscle alterations. A model considering the above parameters may classify more accurately over 30% of the patients.

A cost analysis of a broad-spectrum antibiotic therapy in the empirical treatment of health care-associated infections in cirrhotic patients.

BACKGROUND: Early diagnosis and appropriate treatment of infections in cirrhosis are crucial. As new guidelines in this context, particularly for health care-associated (HCA) infections, would be needed, we performed a trial documenting whether an empirical broad-spectrum antibiotic therapy is more effective than the standard one for these infections. Because of the higher daily cost of broad-spectrum than standard antibiotics, we performed a cost analysis to compare: 1) total drug costs, 2) profitability of hospital admissions. METHODS: This retrospective observational analysis was performed on patients enrolled in the trial NCT01820026, in which consecutive cirrhotic patients with HCA infections were randomly assigned to a standard vs a broad-spectrum treatment. Antibiotic daily doses, days of treatment, length of hospital stay, and DRG (diagnosis-related group) were recorded from the clinical trial medical records. The profitability of hospitalizations was calculated considering DRG tariffs divided by length of hospital stay. RESULTS: We considered 84 patients (42 for each group). The standard therapy allowed to obtain a first-line treatment cost lower than in the broad-spectrum therapy. Anyway, the latter, being related to a lower failure rate (19% vs 57.1%), resulted in cost saving in terms of cumulative antibiotic costs (first- and second-line treatments). The mean cost saving per patient for the broad-spectrum arm was €44.18 (-37.6%), with a total cost saving of about €2,000. Compared to standard group, we observed a statistically significant reduction in hospital stay from 17.8 to 11.8 days (p<0.002) for patients treated with broad-spectrum antibiotics. The distribution of DRG tariffs was similar in the two groups. According to DRG, the shorter length of hospital stay of the broad-spectrum group involved a higher mean profitable daily cost than standard group (€345.61 vs €252.23; +37%). CONCLUSION: Our study supports the idea that the use of a broad-spectrum empirical treatment for HCA infections in cirrhosis would be cost-saving and that hospitals need to be aware of the clinical and economic consequences of a wrong antibiotic treatment in this setting.

The spread of multi drug resistant infections is leading to an increase in the empirical antibiotic treatment failure in cirrhosis: a prospective survey.

BACKGROUND: The spread of multi-resistant infections represents a continuously growing problem in cirrhosis, particularly in patients in contact with the healthcare environment. AIM: Our prospective study aimed to analyze epidemiology, prevalence and risk factors of multi-resistant infections, as well as the rate of failure of empirical antibiotic therapy in cirrhotic patients. METHODS: All consecutive cirrhotic patients hospitalized between 2008 and 2013 with a microbiologically-documented infection (MDI) were enrolled. Infections were classified as Community-Acquired (CA), Hospital-Acquired (HA) and Healthcare-Associated (HCA). Bacteria were classified as Multidrug-Resistant (MDR) if resistant to at least three antimicrobial classes, Extensively-Drug-Resistant (XDR) if only sensitive to one/two classes and Pandrug-Resistant (PDR) if resistant to all classes. RESULTS: One-hundred-twenty-four infections (15% CA, 52% HA, 33% HCA) were observed in 111 patients. Urinary tract infections, pneumonia and spontaneous bacterial peritonitis were the more frequent. Forty-seven percent of infections were caused by Gram-negative bacteria. Fifty-one percent of the isolates were multi-resistant to antibiotic therapy (76% MDR, 21% XDR, 3% PDR): the use of antibiotic prophylaxis (OR = 8.4; 95%CI = 1.03-76; P = 0,05) and current/recent contact with the healthcare-system (OR = 3.7; 95%CI = 1.05-13; P = 0.04) were selected as independent predictors. The failure of the empirical antibiotic therapy was progressively more frequent according to the degree of resistance. The therapy was inappropriate in the majority of HA and HCA infections. CONCLUSIONS: Multi-resistant infections are increasing in hospitalized cirrhotic patients. A better knowledge of the epidemiological characteristics is important to improve the efficacy of empirical antibiotic therapy. The use of preventive measures aimed at reducing the spread of multi-resistant bacteria is also essential.

Sarcopenia in liver cirrhosis: the role of computed tomography scan for the assessment of muscle mass compared with dual-energy X-ray absorptiometry and anthropometry.

BACKGROUND: Sarcopenia evaluated by computed tomography (CT) scan at the lumbar site has been identified as a risk factor for morbidity and mortality in cirrhosis. AIM: The aim of this study was to compare the measurement of muscle mass through CT scan, considered the gold standard, with other reliable techniques to evaluate the rate of agreement between different available methods for the assessment of muscle mass in cirrhosis. The correlation between measurements of muscle mass and of muscle strength was also investigated. PATIENTS AND METHODS: Adult patients eligible for liver transplantation were studied. Lumbar skeletal muscle cross-sectional area was measured by CT and muscle depletion was defined using previously published cut-offs. Mid-arm muscle circumference was calculated following anthropometric measures. The Fat-Free Mass Index and the Appendicular Skeletal Muscle Index were calculated using dual-energy X-ray absorptiometry. Muscle strength was evaluated using the Hand Grip test. RESULTS: Fifty-nine patients with cirrhosis were included. Sarcopenia was diagnosed in 76% of the patients according to CT evaluation. A significant reduction in Fat-Free Mass Index and Appendicular Skeletal Muscle Index was observed in 42-52% of the patients, whereas 52% showed a mid-arm muscle circumference less than 10th percentile. Skeletal muscle mass evaluation through CT was only weakly correlated with dual-energy X-ray absorptiometry and anthropometry evaluation. No correlation was observed between CT measurement of muscle mass and Hand Grip test. CONCLUSION: CT scan can identify the highest percentage of sarcopenia in cirrhosis and no other techniques are actually available as a replacement. Future efforts should focus on approaches for assessing both skeletal muscle mass and function to provide a better evaluation of sarcopenia in cirrhotic patients.