Leroy R. Thacker

Linkage of gut microbiome with cognition in hepatic encephalopathy

Hepatic encephalopathy (HE) has been related to gut bacteria and inflammation in the setting of intestinal barrier dysfunction. We aimed to link the gut microbiome with cognition and inflammation in HE using a systems biology approach. Multitag pyrosequencing (MTPS) was performed on stool of cirrhotics and age-matched controls. Cirrhotics with/without HE underwent cognitive testing, inflammatory cytokines, and endotoxin analysis. Patients with HE were compared with those without HE using a correlation-network analysis. A select group of patients with HE (n = 7) on lactulose underwent stool MTPS before and after lactulose withdrawal over 14 days. Twenty-five patients [17 HE (all on lactulose, 6 also on rifaximin) and 8 without HE, age 56 ± 6 yr, model for end-stage liver disease score 16 ± 6] and ten controls were included. Fecal microbiota in cirrhotics were significantly different (higher Enterobacteriaceae, Alcaligeneceae, and Fusobacteriaceae and lower Ruminococcaceae and Lachnospiraceae) compared with controls. We found altered flora (higher Veillonellaceae), poor cognition, endotoxemia, and inflammation (IL-6, TNF-α, IL-2, and IL-13) in HE compared with cirrhotics without HE. In the cirrhosis group, Alcaligeneceae and Porphyromonadaceae were positively correlated with cognitive impairment. Fusobacteriaceae, Veillonellaceae, and Enterobacteriaceae were positively and Ruminococcaceae negatively related to inflammation. Network-analysis comparison showed robust correlations (all P < 1E-5) only in the HE group between the microbiome, cognition, and IL-23, IL-2, and IL-13. Lactulose withdrawal did not change the microbiome significantly beyond Fecalibacterium reduction. We concluded that cirrhosis, especially when complicated with HE, is associated with significant alterations in the stool microbiome compared with healthy individuals. Specific bacterial families (Alcaligeneceae, Porphyromonadaceae, Enterobacteriaceae) are strongly associated with cognition and inflammation in HE.

Modulation of the fecal bile acid profile by gut microbiota in cirrhosis.

BACKGROUND & AIMS The 7α-dehydroxylation of primary bile acids (BAs), chenodeoxycholic (CDCA) and cholic acid (CA) into the secondary BAs, lithocholic (LCA) and deoxycholic acid (DCA), is a key function of the gut microbiota. We aimed at studying the linkage between fecal BAs and gut microbiota in cirrhosis since this could help understand cirrhosis progression. METHODS Fecal microbiota were analyzed by culture-independent multitagged-pyrosequencing, fecal BAs using HPLC and serum BAs using LC-MS in controls, early (Child A) and advanced cirrhotics (Child B/C). A subgroup of early cirrhotics underwent BA and microbiota analysis before/after eight weeks of rifaximin. RESULTS Cross-sectional: 47 cirrhotics (24 advanced) and 14 controls were included. In feces, advanced cirrhotics had the lowest total, secondary, secondary/primary BA ratios, and the highest primary BAs compared to early cirrhotics and controls. Secondary fecal BAs were detectable in all controls but in a significantly lower proportion of cirrhotics (p<0.002). Serum primary BAs were higher in advanced cirrhotics compared to the rest. Cirrhotics, compared to controls, had a higher Enterobacteriaceae (potentially pathogenic) but lower Lachonospiraceae, Ruminococcaceae and Blautia (7α-dehydroxylating bacteria) abundance. CDCA was positively correlated with Enterobacteriaceae (r=0.57, p<0.008) while Ruminococcaceae were positively correlated with DCA (r=0.4, p<0.05). A positive correlation between Ruminococcaceae and DCA/CA (r=0.82, p<0.012) and Blautia with LCA/CDCA (r=0.61, p<0.03) was also seen. Prospective study: post-rifaximin, six early cirrhotics had reduction in Veillonellaceae and in secondary/primary BA ratios. CONCLUSIONS Cirrhosis, especially advanced disease, is associated with a decreased conversion of primary to secondary fecal BAs, which is linked to abundance of key gut microbiome taxa.

Second infections independently increase mortality in hospitalized patients With cirrhosis: the north american consortium for the study of end‐stage liver disease (NACSELD) experience

Bacterial infections are an important cause of mortality in cirrhosis, but there is a paucity of multicenter studies. The aim was to define factors predisposing to infection‐related mortality in hospitalized patients with cirrhosis. A prospective, cohort study of patients with cirrhosis with infections was performed at eight North American tertiary‐care hepatology centers. Data were collected on admission vitals, disease severity (model for endstage liver disease [MELD] and sequential organ failure [SOFA] scores), first infection site, type (community‐acquired, healthcare‐associated [HCA] or nosocomial), and second infection occurrence during hospitalization. The outcome was mortality within 30 days. A multivariate logistic regression model predicting mortality was created. 207 patients (55 years, 60% men, MELD 20) were included. Most first infections were HCA (71%), then nosocomial (15%) and community‐acquired (14%). Urinary tract infections (52%), spontaneous bacterial peritonitis (SBP, 23%) and spontaneous bacteremia (21%) formed the majority of the first infections. Second infections were seen in 50 (24%) patients and were largely preventable: respiratory, including aspiration (28%), urinary, including catheter‐related (26%), fungal (14%), and Clostridium difficile (12%) infections. Forty‐nine patients (23.6%) who died within 30 days had higher admission MELD (25 versus 18, P < 0.0001), lower serum albumin (2.4 g/dL versus 2.8 g/dL, P = 0.002), and second infections (49% versus 16%, P < 0.0001) but equivalent SOFA scores (9.2 versus 9.9, P = 0.86). The case fatality rate was highest for C. difficile (40%), respiratory (37.5%), and spontaneous bacteremia (37%), and lowest for SBP (17%) and urinary infections (15%). The model for mortality included admission MELD (odds ratio [OR]: 1.12), heart rate (OR: 1.03) albumin (OR: 0.5), and second infection (OR: 4.42) as significant variables. Conclusion: Potentially preventable second infections are predictors of mortality independent of liver disease severity in this multicenter cirrhosis cohort. (HEPATOLOGY 2012;56:2328–2335)

Survival in infection-related acute-on-chronic liver failure is defined by extrahepatic organ failures

Infections worsen survival in cirrhosis; however, simple predictors of survival in infection‐related acute‐on‐chronic liver failure (I‐ACLF) derived from multicenter studies are required in order to improve prognostication and resource allocation. Using the North American Consortium for Study of End‐stage Liver Disease (NACSELD) database, data from 18 centers were collected for survival analysis of prospectively enrolled cirrhosis patients hospitalized with an infection. We defined organ failures as 1) shock, 2) grade III/IV hepatic encephalopathy (HE), 3) need for dialysis and mechanical ventilation. Determinants of survival with these organ failures were analyzed. In all, 507 patients were included (55 years, 52% hepatitis C virus [HCV], 15.8% nosocomial infection, 96% Child score ≥7) and 30‐day evaluations were available in 453 patients. Urinary tract infection (UTI) (28.5%), and spontaneous bacterial peritonitis (SBP) (22.5%) were the most prevalent infections. During hospitalization, 55.7% developed HE, 17.6% shock, 15.1% required renal replacement, and 15.8% needed ventilation; 23% died within 30 days and 21.6% developed second infections. Admitted patients developed none (38.4%), one (37.3%), two (10.4%), three (10%), or four (4%) organ failures. The 30‐day survival worsened with a higher number of extrahepatic organ failures, none (92%), one (72.6%), two (51.3%), three (36%), and all four (23%). I‐ACLF was defined as ≥2 organ failures given the significant change in survival probability associated at this cutoff. Baseline independent predictors for development of ACLF were nosocomial infections, Model for Endstage Liver Disease (MELD) score, low mean arterial pressure (MAP), and non‐SBP infections. Independent predictors of poor 30‐day survival were I‐ACLF, second infections, and admission values of high MELD, low MAP, high white blood count, and low albumin. Conclusion: Using multicenter study data in hospitalized decompensated infected cirrhosis patients, I‐ACLF defined by the presence of two or more organ failures using simple definitions is predictive of poor survival. (Hepatology 2014;60:250–256)

The Multi-Dimensional Burden of Cirrhosis and Hepatic Encephalopathy on Patients and Caregivers

OBJECTIVES:Cirrhosis and hepatic encephalopathy (HE) can adversely affect survival, but their effect on socioeconomic and emotional burden on the family is not clear. The aim was to study the emotional and socioeconomic burden of cirrhosis and HE on patients and informal caregivers.METHODS:A cross-sectional study in two transplant centers (Veterans and University) of cirrhotic patients and their informal caregivers was performed. Demographics for patient/caregivers, model-for-end-stage liver disease (MELD) score, and cirrhosis complications were recorded. Patients underwent a cognitive battery, sociodemographic, and financial questionnaires. Caregivers were given the perceived caregiver burden (PCB; maximum=155) and Zarit Burden Interview (ZBI)-Short Form (maximum=48) and questionnaires for depression, anxiety, and social support.RESULTS:A total of 104 cirrhotics (70% men, 44% previous HE, median MELD 12, 49% veterans) and their caregivers (66% women, 77% married, relationship duration 32±14 years) were included. Cirrhosis severely impacted the family unit with respect to work (only 56% employed), finances, and adherence. Those with previous HE had worse unemployment (87.5 vs. 19%, P=0.0001) and financial status (85 vs. 61%, P=0.019) and posed a higher caregiver burden; PCB (75 vs. 65, P=0.019) and ZBI (16 vs. 11, P=0.015) compared with others. Cognitive performance and MELD score were significantly correlated with employment and caregiver burden. Veterans and non-veterans were equally affected. On regression, depression score, MELD, and cognitive tests predicted both PCB and ZBI score.CONCLUSIONS:Previous HE and cognitive dysfunction are associated with worse employment, financial status, and caregiver burden. Cirrhosis-related expenses impact the family units daily functioning and medical adherence. A multidisciplinary approach to address this burden is required.

New Consensus Definition of Acute Kidney Injury Accurately Predicts 30-Day Mortality in Patients With Cirrhosis and Infection

BACKGROUND & AIMS Participants at a consensus conference proposed defining cirrhosis-associated acute kidney injury (AKI) based on a >50% increase in serum creatinine level from the stable baseline value in <6 months or an increase of ≥ 0.3 mg/dL in <48 hours. We performed a prospective study to evaluate the ability of these criteria to predict mortality within 30 days of hospitalization among patients with cirrhosis and infection. METHODS We followed up 337 patients with cirrhosis who were admitted to the hospital with an infection or developed an infection during hospitalization (56% men; 56 ± 10 years of age; Model for End-Stage Liver Disease [MELD] score, 20 ± 8) at 12 centers in North America. We compared data on 30-day mortality, length of stay in the hospital, and organ failure between patients with and without AKI. RESULTS In total, based on the consensus criteria, 166 patients (49%) developed AKI during hospitalization. Patients who developed AKI were admitted with higher Child-Pugh scores than those who did not develop AKI (11.0 ± 2.1 vs 9.6 ± 2.1; P < .0001) as well as higher MELD scores (23 ± 8 vs 17 ± 7; P < .0001) and lower mean arterial pressure (81 ± 16 vs 85 ± 15 mm Hg; P < .01). Higher percentages of patients with AKI died within 30 days of hospitalization (34% vs 7%), were transferred to the intensive care unit (46% vs 20%), required ventilation (27% vs 6%), or went into shock (31% vs 8%); patients with AKI also had longer stays in the hospital (17.8 ± 19.8 vs 13.3 ± 31.8 days) (all P < .001). Of the AKI episodes, 56% were transient, 28% were persistent, and 16% resulted in dialysis. Mortality was higher among those without renal recovery (80%) compared with partial (40%) or complete recovery (15%) or those who did not develop AKI (7%; P < .0001). CONCLUSIONS Among patients with cirrhosis, 30-day mortality is 10-fold higher among those with irreversible AKI than those without AKI. The consensus definition of AKI accurately predicts 30-day mortality, length of hospital stay, and organ failure.

Effects of tacrolimus on hyperlipidemia after successful renal transplantation: A southeastern organ procurement foundation multicenter clinical study

BACKGROUND Tacrolimus has been shown to have a less adverse effect on the lipid profiles of transplant patients when the drug is started as induction therapy. In order to determine the effect tacrolimus has on lipid profiles in stable cyclosporine-treated renal transplant patients with established hyperlipidemia, a randomized prospective study was undertaken by the Southeastern Organ Procurement Foundation. METHODS Patients of the 13 transplant centers, with cholesterol of 240 mg/dl or greater, who were at least 1 year posttransplant with stable renal function, were randomly assigned to remain on cyclosporine (control) or converted to tacrolimus. Patients converted to tacrolimus were maintained at a level of 5-15 ng/ml, and control patients remained at their previous levels of cyclosporine. Concurrent immunosuppressants were not changed. Levels of total cholesterol, triglycerides, total high-density lipoprotein, low-density lipoprotein (LDL), very-low-density lipoprotein, and apoproteins A and B were monitored before conversion and at months 1, 3, and 6. Renal function and glucose control were evaluated at the beginning and end of the study (month 6). RESULTS A total of 65 patients were enrolled; 12 patients failed to complete the study. None were removed as a result of acute rejection or graft failure. Fifty-three patients were available for analysis (27 in the tacrolimus group and 26 controls). Demographics were not different between groups. In patients converted to tacrolimus treatment, there was a -55 mg/dl (-16%) (P=0.0031) change in cholesterol, a -48 mg/dl (-25%) (P=0.0014) change in LDL cholesterol, and a -36 mg/dl (-23%) (P=0.034) change in apolipoprotein B. There was no change in renal function, glycemic control, or incidence of new onset diabetes mellitus in the tacrolimus group. CONCLUSION Conversion from cyclosporine to tacrolimus can be safely done after successful transplantation. Introduction of tacrolimus to a stable renal patient does not effect renal function or glycemic control. Tacrolimus can lower cholesterol, LDL, and apolipoprotein B. Conversion to tacrolimus from cyclosporine should be considered in the treatment of posttransplant hyperlipidemia.

Original ResearchFull Report: Clinical—LiverNew Consensus Definition of Acute Kidney Injury Accurately Predicts 30-Day Mortality in Patients With Cirrhosis and Infection

BACKGROUND & AIMS Participants at a consensus conference proposed defining cirrhosis-associated acute kidney injury (AKI) based on a >50% increase in serum creatinine level from the stable baseline value in <6 months or an increase of ≥ 0.3 mg/dL in <48 hours. We performed a prospective study to evaluate the ability of these criteria to predict mortality within 30 days of hospitalization among patients with cirrhosis and infection. METHODS We followed up 337 patients with cirrhosis who were admitted to the hospital with an infection or developed an infection during hospitalization (56% men; 56 ± 10 years of age; Model for End-Stage Liver Disease [MELD] score, 20 ± 8) at 12 centers in North America. We compared data on 30-day mortality, length of stay in the hospital, and organ failure between patients with and without AKI. RESULTS In total, based on the consensus criteria, 166 patients (49%) developed AKI during hospitalization. Patients who developed AKI were admitted with higher Child-Pugh scores than those who did not develop AKI (11.0 ± 2.1 vs 9.6 ± 2.1; P < .0001) as well as higher MELD scores (23 ± 8 vs 17 ± 7; P < .0001) and lower mean arterial pressure (81 ± 16 vs 85 ± 15 mm Hg; P < .01). Higher percentages of patients with AKI died within 30 days of hospitalization (34% vs 7%), were transferred to the intensive care unit (46% vs 20%), required ventilation (27% vs 6%), or went into shock (31% vs 8%); patients with AKI also had longer stays in the hospital (17.8 ± 19.8 vs 13.3 ± 31.8 days) (all P < .001). Of the AKI episodes, 56% were transient, 28% were persistent, and 16% resulted in dialysis. Mortality was higher among those without renal recovery (80%) compared with partial (40%) or complete recovery (15%) or those who did not develop AKI (7%; P < .0001). CONCLUSIONS Among patients with cirrhosis, 30-day mortality is 10-fold higher among those with irreversible AKI than those without AKI. The consensus definition of AKI accurately predicts 30-day mortality, length of hospital stay, and organ failure.

Improvement in Oncology Practice Performance Through Voluntary Participation in the Quality Oncology Practice Initiative

PURPOSE The Quality Oncology Practice Initiative (QOPI) became available to all American Society of Clinical Oncology member physicians in 2006 as a voluntary medical oncology practice-based quality measurement and improvement project. QOPI assesses practice performance for a series of evidence- and consensus-based process measures, relying on practices to complete structured chart reviews and submit data via a secure Web-based portal. METHODS This analysis focused on the 71 practices that participated in both the March and September 2006 data collections (7,624 charts abstracted in March and 10,240 in September). Among 33 measures common to both collections, five measures were closely correlated, and 28 are included in the final analysis. Composite scores were created for six different domains of care. Statistical significance was tested on both absolute changes and relative changes (relative failure reduction) of quality measures from baseline to follow-up and between the lower quartile and all other quartiles. RESULTS Practice performance on individual measures varied between 18.8% and 98.6%. Mean overall performance as measured by a composite score increased from 78.7% in March to 82.3% in September (P < .05). Improvement was most marked among practices originally performing in the bottom quartile. Using a composite score, the absolute and relative performance for the bottom quartile improved by 27% and 35%, respectively, statistically superior to that of all others. CONCLUSION Practices that participated in QOPI demonstrated improved performance in self-reported process measures, with the greatest improvement demonstrated in initially low-performing practices.

Randomised clinical trial: Lactobacillus GG modulates gut microbiome, metabolome and endotoxemia in patients with cirrhosis.

Safety of individual probiotic strains approved under Investigational New Drug (IND) policies in cirrhosis with minimal hepatic encephalopathy (MHE) is not clear.