Cell-Based Regeneration and Treatment of Liver Diseases.

The liver, in combination with a functional biliary system, is responsible for maintaining a great number of vital body functions. However, acute and chronic liver diseases may lead to irreversible liver damage and, ultimately, liver failure. At the moment, the best curative option for patients suffering from end-stage liver disease is liver transplantation. However, the number of donor livers required by far surpasses the supply, leading to a significant organ shortage. Cellular therapies play an increasing role in the restoration of organ function and can be integrated into organ transplantation protocols. Different types and sources of stem cells are considered for this purpose, but highly specific immune cells are also the focus of attention when developing individualized therapies. In-depth knowledge of the underlying mechanisms governing cell differentiation and engraftment is crucial for clinical implementation. Additionally, novel technologies such as ex vivo machine perfusion and recent developments in tissue engineering may hold promising potential for the implementation of cell-based therapies to restore proper organ function.

Systemic inflammation increases across distinct stages of advanced chronic liver disease and correlates with decompensation and mortality.

BACKGROUND & AIMS: Distinct prognostic stages of advanced chronic liver disease (ACLD) are defined by severity of portal hypertension (PH) and the presence/absence of clinical complications. We characterised the degree of liver dysfunction, PH, and systemic inflammation across the distinct prognostic stages and assessed their relative impact on decompensation and mortality. METHODS: A single-centre, prospective cohort of ACLD patients undergoing hepatic venous pressure gradient (HVPG) measurement between 01/2017 and 08/2019 were classified into 6 prognostic stages: mild PH (HVPG 6-9 mmHg, S0), clinically significant PH (HVPG ≥10 mmHg without varices, S1), presence of varices (S2), history of variceal bleeding (S3), first non-bleeding decompensation (S4), and further decompensation (S5). The model for end-stage liver disease (MELD), C-reactive protein (CRP), and IL-6 levels were assessed in relation to their predictive value for decompensation and death. RESULTS: Among 168 ACLD patients 78 had compensated (cACLD, S0 = 13; S1 = 21; S2 = 44) and 90 had decompensated (dACLD, S3 = 10; S4 = 58; S5 = 22) disease. MELD increased across all stages (p <0.001), whereas HVPG mostly increased within cACLD substages. Significant increases in CRP and IL-6 levels were only noted across dACLD substages. IL-6 was an independent predictor of decompensation at 1-year follow-up in cACLD (hazard ratio [HR] 1.06, 95% CI 1.01-1.10; p = 0.013). In dACLD patients, IL-6 levels predicted death/transplantation after 1-year of follow-up (HR 1.02, 95% CI 1.01-1.03; p = 0.004). CONCLUSION: HVPG progression occurs mostly in cACLD patients, whereas systemic inflammation, as reflected by IL-6 levels, only increases substantially across dACLD stages. IL-6 levels correlate with the risk of first decompensation in cACLD and of death/transplantation in dACLD patients. LAY SUMMARY: Patients with advanced chronic liver disease (ACLD; i.e. liver cirrhosis) have a certain risk of mortality according to their stage of disease. Progression of disease is greatly influenced by increased pressure in the portal venous system (i.e. portal hypertension) and occurrence of clinical complications (i.e. decompensation). Our study demonstrates that systemic inflammation markedly increases across highest disease stages, and the inflammation biomarker IL-6 in blood may specifically indicate risk of disease progression in patients with ACLD. CLINICAL TRIALS REGISTRATION: The study is registered at ClinicalTrials.gov (NCT03267615).

Cell therapy for advanced liver diseases: Repair or rebuild.

Advanced liver disease presents a significant worldwide health and economic burden and accounts for 3.5% of global mortality. When liver disease progresses to organ failure the only effective treatment is liver transplantation, which necessitates lifelong immunosuppression and carries associated risks. Furthermore, the shortage of suitable donor organs means patients may die waiting for a suitable transplant organ. Cell therapies have made their way from animal studies to a small number of early clinical trials. Herein, we review the current state of cell therapies for liver disease and the mechanisms underpinning their actions (to repair liver tissue or rebuild functional parenchyma). We also discuss cellular therapies that are on the clinical horizon and challenges that must be overcome before routine clinical use is a possibility.

The Impact of Performance Status on Length of Hospital Stay and Clinical Complications Following Liver Transplantation.

BACKGROUND: Impaired pretransplant performance status (PS) is associated with chronic liver disease (CLD). We studied its impact on hospital length of stay (LOS), complications, and readmissions in the first year after liver transplantation. METHODS: The Standard National Liver Transplant Registry was linked to a hospital administrative dataset, and all first-time liver transplant recipients with CLD aged ≥18 years in England were identified. A modified 3-level Eastern Cooperative Oncology Group score was used to assess PS. Linear- and logistic-fixed effect regression models were used to estimate the effect of specific posttransplant complications and readmissions in the first year after transplantation. RESULTS: Six thousand nine hundred sixty-eight recipients were included. Impaired PS was associated with an increased LOS in the initial posttransplant period (comparing ECOG 1-3, adjusted difference 7.2 d; 95% confidence [CI], 4.8-9.6; P < 0.001) and in time spent on the ITU (adjusted difference 1.2 d; 95% CI, 0.4-2.0; P < 0.001). There was no significant association between ECOG status and total LOS of later admissions (adjusted difference, 2.5 d; 95% CI, -0.4-5.5; P = 0.23). Those with a poorer ECOG status had an increased incidence of renal failure (odds ratio, 1.5; 95% CI, 1.1-2.0; P = 0.004) and infection (odds ratio, 1.2; 95% CI, 1.1-1.4; P = 0.02) but not an increased incidence of readmission (odds ratio, 1.2; 95% CI, 0.9-1.5; P = 0.13). CONCLUSIONS: In liver transplant recipients with CLD, impaired pretransplant PS is associated with prolonged LOS in the immediate posttransplant period but not with LOS of later admissions in the first year after transplantation. Impaired PS increased the risk of renal failure and infection.

Validating a novel score based on interaction between ACLF grade and MELD score to predict waitlist mortality.

BACKGROUND & AIMS: Among candidates listed for liver transplant (LT), the model for end-stage liver disease (MELD) score may not capture acute-on-chronic liver failure (ACLF) severity. Data on the interaction between ACLF and MELD score in predicting waitlist mortality are scarce. METHODS: We analyzed the UNOS database (01/2002 to 06/2018) for LT listings in adults with cirrhosis and ACLF (without hepatocellular carcinoma). ACLF grades 1, 2, 3a, and 3b- were defined using the modified EASL-CLIF criteria. RESULTS: Of 18,416 candidates with ACLF at listing (mean age 54 years, 69% males, 63% Caucasians), 90-day waitlist mortality (patient death or being too sick for LT) was 21.6% (18%, 20%, 25%, and 39% for ACLF grades 1, 2, 3a, and 3b, respectively). Using a Fine and Gray regression model, we identified an interaction between MELD and ACLF grade, with ACLF having a higher impact at lower MELD scores. Other variables included candidate's age, sex, liver disease etiology, listing MELD, ACLF grade, obesity, and performance status. A score developed using parameter estimates from the interaction model on the derivation cohort (n = 9,181) stratified the validation cohort (n = 9,235) into quartiles: Q1 (score <10.42), Q2 (10.42-12.81), Q3 (12.82-15.50), and Q4 (>15.50). Waitlist mortality increased with each quartile from 13%, 18%, 23%, and 36%, respectively. Observed vs. expected waitlist mortality deciles in the validation cohort showed good calibration (goodness of fit p = 0.98) and correlation (R = 0.99). CONCLUSION: Among selected candidates who have ACLF at listing, MELD score and ACLF interact in predicting cumulative risk of 90-day waitlist mortality, with higher impact of ACLF grade at lower listing MELD score. Validating these findings in large prospective studies will support consideration of both MELD and ACLF when prioritizing transplant candidates and allocating liver grafts. LAY SUMMARY: In patients with cirrhosis listed for liver transplantation, the presence of multiorgan failure, a condition referred to as acute-on-chronic liver failure, is associated with high waiting list mortality rates. Current organ allocation policy disadvantages patients with this condition. This study describes and validates a new scoring method that performs better than the currently available scoring systems. Further validation of this approach may reduce the deaths of patients with cirrhosis and acute-on-chronic liver failure on the transplant waiting list.

Single center analysis of therapy and outcomes of hepatocellular carcinoma in Sub-Saharan Africa.

PURPOSE: To evaluate the characteristics and response to therapy for HCC in sub-Saharan Africa. PATIENTS AND METHODS: We retrospectively evaluated demographic, clinical and outcome variables of HCC in a referral clinic in Ethiopia from 2016 to 2018. Survival assessment was performed using the Mann-Whitney test. Associations between categorical variables was assessed using Pearson Chi-square test. RESULTS: We report 46 HCC cases with a median age of 54 years (IQR 45-62) and 50% female. Viral hepatitis was the most common underlying etiology, with 41% of subjects infected with hepatitis B virus (HBV) and 45% with hepatitis C. The median MELD was 12 (IQR 8-17), we found no association between survival and a MELD score 15, regardless of underlying disease (pr=0.61, p>0.05). 31% of individuals underwent supportive treatment with a median survival of 27 days (IQR 19-181), 18% used Sorafenib (median survival of 94 days, IQR 24-121), and trans-arterial chemoembolization (TACE) was utilized in 16% (median survival of 352 days, IQR 30-436). HBV cases were diagnosed younger (31% before the age of 40) and those on Tenofovir had a longer median survival than those off Tenofovir (121 vs 34 days). CONCLUSION: Our study found that antiviral treatment of HBV infection was associated with longer survival in HCC. Furthermore, Sorafenib seemed beneficial in patients that used this modality and NLR was a good prognostic factor.

A 2020 update on liver transplant for hepatocellular carcinoma.

INTRODUCTION: Hepatocellular carcinoma is the most frequent liver tumor and is associated with chronic liver disease in 90% of cases. In selected cases, liver transplantation represents an effective therapy with excellent overall survival. AREA COVERED: Since the introduction of Milan criteria in 1996, numerous alternative selection systems to LT for HCC patients have been proposed. Debate remains about how best to select HCC patients for transplant and how to prioritize them on the waiting list. EXPERT OPINION: The selection of the best scoring system to propose in the context of LT for HCC is far to be identified. In this review, we analyze and categorize the various selection systems, assessing their roles in the different decisional phases.

The imperative for an updated cirrhosis surgical risk score.

The burden of cirrhosis is increasing, as is the need for surgeries in patients with cirrhosis. These patients have increased surgical risk relative to non-cirrhotic patients. Unfortunately, currently available cirrhosis surgical risk prediction tools are non-specific, poorly calibrated, limited in scope, and/or outdated. The Mayo score is the only dedicated tool to provide discrete post-operative mortality predictions for patients with cirrhosis, however it has several limitations. First, its single-center nature does not reflect institution-specific practices that may impact surgical risk. Second, it pre-dates major surgical changes that have changed the landscape of patient selection and surgical risk. Third, it has been shown to overestimate risk in external validation. Finally, and perhaps most importantly, the score does not account for differences in risk based on surgery type. The clinical consequences of inaccurate prediction and risk overestimation are significant, as patients with otherwise acceptable risk may be denied elective surgical procedures, thereby increasing their future need for higher-risk emergent procedures. Confident evaluation of the risks and benefits of surgery in this growing population requires an updated, generalizable, and accurate cirrhosis surgical risk calculator that incorporates the type of surgery under consideration.

Comparison between criteria for diagnosing malnutrition in patients with advanced chronic liver disease: GLIM group proposal versus different nutritional screening tools.

BACKGROUND: Different nutritional screening instruments can be used to identify the risk of malnutrition in advanced chronic liver disease patients. The present study aimed to evaluate and compare two nutrition screening tools with the Global Leadership Initiative on Malnutrition (GLIM) diagnostic criteria for malnutrition in patients with advanced chronic liver disease. METHODS: Two nutritional screening tools, Nutritional Risk Screening 2002 (NRS-2002) and Royal Free Hospital Nutritional Prioritizing Tool (RFH-NPT), were assessed for 166 patients with liver cirrhosis. We compared medium/high nutritional risk screening with the diagnosis of malnutrition, using the GLIM criteria as the reference standard. RESULTS: According to the GLIM criteria, 57.3% of the patients were malnourished. NRS and RFH-NPT identified, respectively, 36.1% and 52.4% of patients with nutritional risk. RFH-NPT presented better agreement with the diagnosis according to GLIM criteria (k = 0.64; 95% confidence interval = 0.52-0.75), higher sensitivity (80%), higher negative predictive value (79%) and larger area under the curve (82.3%) compared to the NRS. CONCLUSIONS: RFH-NPT, when compared with the GLIM method, has substantial agreement in identifying nutritional risk, good sensitivity and good value for diagnosing malnutrition in patients with advanced chronic liver disease.

Regulation of histamine and diamine oxidase in patients undergoing orthotopic liver transplantation.

Increased concentrations of the vasodilator histamine have been observed in patients undergoing abdominal surgery. The role of histamine during orthotopic liver transplantation (OLT) has only been studied in animals. The aim of this study was to measure plasma concentrations of histamine and its degrading enzyme diamine oxidase (DAO) in patients undergoing orthotopic liver transplantation, and assess whether histamine or DAO correlate with intraoperative noradrenaline requirements. Histamine and DAO concentrations were measured in 22 adults undergoing liver transplantation and 22 healthy adults. Furthermore, norepinephrine requirements during liver transplantation were recorded. Baseline concentrations of histamine and DAO were greater in patients, who underwent liver transplantation, than in healthy individuals (Histamine: 6.4 nM, IQR[2.9-11.7] versus 4.3 nM, IQR[3.7-7.1], p = 0.029; DAO: 2.0 ng/mL, IQR[1.5-4.1] versus <0,5 ng/mL, IQR[<0.5-1.1], p < 0.001). During liver transplantation, histamine concentrations decreased to 1.8 nM, IQR[0.5-4.9] in the anhepatic phase (p < 0.0001 versus baseline), and to 1.5 nM, IQR[0.5-2.9] after reperfusion (p < 0.0001 versus baseline). In contrast, DAO concentrations increased to 35.5 ng/ml, IQR[20-50] in the anhepatic phase (p = 0.001 versus baseline) and to 39.5 ng/ml, IQR[23-64] after reperfusion (p = 0.001 versus baseline), correlating inversely with histamine. Norepinephrine requirements during human liver transplantation correlated significantly with DAO concentrations in the anhepatic phase (r = 0.58, p = 0.011) and after reperfusion (r = 0.56; p = 0.022). In patients undergoing orthotopic liver transplantation, histamine concentrations decrease whereas DAO concentrations increase manifold. Diamine oxidase correlates with intraoperative norepinephrine requirements in patients undergoing OLT.

Liver Progenitors and Adult Cell Plasticity in Hepatic Injury and Repair: Knowns and Unknowns.

The liver is a complex organ performing numerous vital physiological functions. For that reason, it possesses immense regenerative potential. The capacity for repair is largely attributable to the ability of its differentiated epithelial cells, hepatocytes and biliary epithelial cells, to proliferate after injury. However, in cases of extreme acute injury or prolonged chronic insult, the liver may fail to regenerate or do so suboptimally. This often results in life-threatening end-stage liver disease for which liver transplantation is the only effective treatment. In many forms of liver injury, bipotent liver progenitor cells are theorized to be activated as an additional tier of liver repair. However, the existence, origin, fate, activation, and contribution to regeneration of liver progenitor cells is hotly debated, especially since hepatocytes and biliary epithelial cells themselves may serve as facultative stem cells for one another during severe liver injury. Here, we discuss the evidence both supporting and refuting the existence of liver progenitor cells in a variety of experimental models. We also debate the validity of developing therapies harnessing the capabilities of these cells as potential treatments for patients with severe and chronic liver diseases.

Effects of Intraoperative Fluid Balance During Liver Transplantation on Postoperative Acute Kidney Injury: An Observational Cohort Study.

BACKGROUND: Liver transplant recipients suffer many postoperative complications. Few studies evaluated the effects of fluid management on these complications. We conducted an observational cohort study to evaluate the association between intraoperative fluid balance and postoperative acute kidney injury (AKI) and other postoperative complications. METHODS: We included consecutive adult liver transplant recipients who had their surgery between July 2008 and December 2017. Our exposure was intraoperative fluid balance, and our primary outcome was the grade of AKI at 48 hours after surgery. Our secondary outcomes were the grade of AKI at 7 days, the need for postoperative renal replacement therapy, postoperative red blood cell transfusions, time to first extubation, time to discharge from the intensive care unit (ICU), and 1-year survival. Every analysis was adjusted for potential confounders. RESULTS: We included 532 transplantations in 492 patients. We observed no effect of fluid balance on either 48-hour AKI, 7-day AKI, or on the need for postoperative renal replacement therapy after adjustments for confounders. A higher fluid balance increased the time to ICU discharge, and increased the risk of dying (hazard ratio = 1.21 [1.04,1.40]). CONCLUSIONS: We observed no association between intraoperative fluid balance and postoperative AKI. Fluid balance was associated with longer time to ICU discharge and lower survival. This study provides insight that might inform the design of a clinical trial on fluid management strategies in this population.

Phase angle as a severity indicator for liver diseases.

OBJECTIVE: The aim of this study was to evaluate the applicability of phase angle (PhA) as a severity indicator of chronic liver diseases. METHODS: We examined the medical records of 54 patients-27 with hepatocellular carcinoma (HCC) and 27 with non-alcoholic fatty liver disease (NAFLD). The patients were ≥18 y of age. Clinical data, such as Child-Pugh and Barcelona Clinic Liver Cancer (HCC), aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis (FIB)-4 (NAFLD), nutritional parameters (body mass index [BMI], handgrip strength [HGS], and bioelectrical impedance [BIA] data) were collected. Nutritional Risk Index (NRI) was calculated. Analysis was performed using Mann-Whitney test and analysis of variance. Simple multiple linear regression for predictions (Child-Pugh in HCC, APRI and FIB-4 in NAFLD). Receiver operating characteristic curve was estimated to search a cutoff for PhA. For survival, we used the Kaplan-Meier estimator. To verify whether PhA affected patients' survival, we used the Mantel-Haenszel. RESULTS: The prevalence of cirrhosis was high in HCC (n = 25) and low in the NAFLD (n = 4). No patient was classified as undernourished based on BMI; however, NRI showed that 74.1% of patients with HCC had nutritional risk. Child-Pugh was positively correlated with the edema index (extracellular water/total body water [ECW/TBW]) and negatively correlated with PhA and HGS. Higher Child-Pugh and BCLC scores were associated with worse NRI. APRI and FIB-4 were positively correlated with weight and BMI. A significant difference between groups was found for the median values of R, ECW/TBW, PhA, HGS, and albumin. There was a trend toward lower survival in patients with HCC, according to the cutoff point of 5.1 degrees for PhA. CONCLUSION: PhA was shown to be an independent prognostic indicator for cirrhosis and may be related to survival in these patients.

Arterial Blood Pressure at Liver Transplant Evaluation Predicts Renal Histology in Candidates With Renal Dysfunction.

Renal dysfunction is common in liver transplantation (LT) candidates, but differentiating between reversible and irreversible renal injury can be difficult. Kidney biopsy might be helpful in differentiating reversible from irreversible renal injury, but it is associated with significant complications. We aimed to identify pre-LT predictors of potentially reversible renal injury using histological information obtained on pre-LT renal biopsy. Data on 128 LT candidates who underwent pre-LT kidney biopsy were retrospectively collected and correlated with renal histological findings. Indications for kidney biopsy were iothalamate glomerular filtration rate (iGFR) ≤40 mL/minute, proteinuria >500 mg/day, and/or hematuria. According to the biopsy diagnosis, patients were grouped into the following categories: normal (n = 13); acute tubular necrosis (ATN; n = 25); membranoproliferative glomerulonephritis (n = 19); minimal histological changes (n = 24); and advanced interstitial fibrosis (IF) and glomerulosclerosis (GS) (n = 47). Compared with patients having advanced IF/GS, patients with normal biopsies and those with ATN had lower systolic blood pressure (SBP) and diastolic blood pressure (DBP) and higher international normalized ratio and total bilirubin levels (<0.05 for all). Both SBP and DBP directly correlated with the degree of IF and GS (R = 0.3, P ≤ 0.02 for all). SBP ≤90 mm Hg was 100% sensitive and 98% specific in correlating with normal biopsies or ATN, whereas SBP ≥140 mm Hg was 22% sensitive and 90% specific in correlating with advanced IF/GS. Model for End-Stage Liver Disease score, serum creatinine, iGFR, urinary sodium excretion, and renal size did not correlate with biopsy diagnosis or degree of IF or GS. In conclusion, SBP at the time of LT evaluation correlates with renal histology, and it should be included along with other clinical and laboratory markers in the decision-making process to list patients with renal dysfunction for LT alone versus simultaneous liver-kidney transplantation.

Mesenchymal Stem Cells in the Adult Human Liver: Hype or Hope?

Chronic liver diseases constitute a significant economic, social, and biomedical burden. Among commonly adopted approaches, only organ transplantation can radically help patients with end-stage liver pathologies. Cell therapy with hepatocytes as a treatment for chronic liver disease has demonstrated promising results. However, quality human hepatocytes are in short supply. Stem/progenitor cells capable of differentiating into functionally active hepatocytes provide an attractive alternative approach to cell therapy for liver diseases, as well as to liver-tissue engineering, drug screening, and basic research. The application of methods generally used to isolate mesenchymal stem cells (MSCs) and maintain them in culture to human liver tissue provides cells, designated here as liver MSCs. They have much in common with MSCs from other tissues, but differ in two aspects-expression of a range of hepatocyte-specific genes and, possibly, inherent commitment to hepatogenic differentiation. The aim of this review is to analyze data regarding liver MSCs, probably another type of liver stem/progenitor cells different from hepatic stellate cells or so-called hepatic progenitor cells. The review presents an analysis of the phenotypic characteristics of liver MSCs, their differentiation and therapeutic potential, methods for isolating these cells from human liver, and discusses issues of their origin and heterogeneity. Human liver MSCs are a fascinating object of fundamental research with a potential for important practical applications.

Surgery in Patients with Portal Hypertension.

Patients with portal hypertension will increasingly present for nontransplant surgery because of the increasing incidence of, and improving long-term survival for, chronic liver disease. Such patients have increased perioperative morbidity and mortality caused by the systemic pathophysiology of liver disease. Preoperative assessment should identify modifiable causes of liver injury and distinguish between compensated and decompensated cirrhosis. Risk stratification, which is crucial to preparing patients and their families for surgery, relies on scores such as Child-Turcotte-Pugh and Model for End-stage Liver Disease to translate disease severity into quantified outcomes predictions. Risk factors for postoperative complications should also be recognized.

Associação da fadiga com capacidade do exercício em pacientes hepatopatas crônicos candidatos a transplante hepático / Association between fatigue and exercise capacity in patients with chronic liver disease awaiting liver transplantation

ABSTRACT BACKGROUND: Fatigue is highly prevalent in end stage liver disease, the studies about its association with exercise capacity in cirrhotic patients before liver are scarse. OBJECTIVE: In this study, we evaluated fatigue in 95 in end stage liver disease patients awaiting transplantation, compared to healthy volunteers, and tested the association between exercise capacity and fatigue. METHODS: Cross-sectional study of patients with chronic liver disease treated at a referral center in Fortaleza, Brazil. Fatigue was quantified with the Fatigue Severity Scale. The patients were submitted to the 6-min walk test, the 6-min step test, the Hospital Anxiety and Depression Scale, C-reative protein measurement and hematocrit count, measurement of dyspnea among other tests. Fatigue data were obtained from healthy individuals for comparison with patients. RESULTS: The mean age of patients was 45.9±12.3 years, and 53.7% were male. Fatigue, anxiety and depression levels were higher among end stage liver disease patients than among controls. A negative correlation was observed between 6 min step test and Fatigue Severity Scale score (r= -0.2; P=0.02) and between hematocrit count and Fatigue Severity Scale score (r= -0.24; P=0.002). Dyspnea on the Borg scale and fatigue were positively correlated (r=31; P=0.002). In the multivariate analysis, low 6-min step test values and high levels of dyspnea were associated with fatigue. CONCLUSION: Fatigue was more prevalent and severe in end stage liver disease patients than in healthy controls. Low 6MST values and high levels of dyspnea were associated with fatigue in this scenario.

RESUMO CONTEXTO: A fadiga é uma queixa comum em indivíduos com doença hepática crônica candidatos a transplante hepático. Estudos sobre sua associação com capacidade do exercício são escassos. OBJETIVO: Avaliar a fadiga de pacientes com hepatopia crônica candidatos a transplante hepático comparando com um grupo de indivíduos saudáveis. Avaliar a associação da fadiga com capacidade de exercício. MÉTODOS: Este é um estudo transversal com pacientes hepatopatas crônicos num centro de referência em Fortaleza, Brasil. Foi utilizado o questionário de gravidade da fadiga. Os pacientes realizaram o teste da caminhada dos 6 min, teste do degrau 6 min, foi aplicada a escala de ansiedade e depressão, foram dosados proteína C reativa e hematócrito. RESULTADO: A idade média dos pacientes foi de 45,9±12,3 anos, sendo que 53,7% eram homens. Os níveis de fadiga e ansiedade e depressão eram maiores entre os pacientes hepatopatas crônicos quando comparados ao grupo controle. Uma correlação inversa foi observada entre fadiga e o teste do degrau (r= -0,2; P=0,02) também entre hematócrito e fadiga (r= -0,24; P=0,002). Houve uma correlação positiva entre dispneia, através da escala de Borg, e fadiga (r=31; P=0,002). Na análise multivariada um baixo desempenho no teste do degrau e um nível maior de dispneia mostraram uma associação com fadiga. CONCLUSÃO: A fadiga é mais frequente entre os pacientes hepatopatas crônicos quando comparados ao grupo controle. O baixo desempenho na capacidade de exercício e uma queixa maior de dispneia apresentaram uma associação com fadiga nestes pacientes.

Perioperative exercise capacity in chronic liver injury patients with hepatocellular carcinoma undergoing hepatectomy.

Dynamic assessment of preoperative exercise capacity may be a useful predictor of postoperative prognosis. We aimed to clarify whether perioperative exercise capacity was related to long-term survival in hepatocellular carcinoma patients with chronic liver injury undergoing hepatectomy. One hundred-six patients with hepatocellular carcinoma underwent pre- and postoperative cardiopulmonary exercise testing to determine their anaerobic threshold, defined as the point between carbon dioxide production and oxygen consumption per unit of time. Testing involved 35 items including blood biochemistry analysis, in-vivo component analysis, dual-energy X-ray absorptiometry, and cardiopulmonary exercise testing preoperatively and 6 months postoperatively. We classified patients with anaerobic threshold ≥ 90% 6 months postoperatively compared with the preoperative level as the maintenance group (n = 78) and patients with anaerobic threshold < 90% as the decrease group (n = 28). Five-year recurrence-free survival rates were 39.9% vs. 9.9% (maintenance vs. decrease group) (hazard ratio: 1.87 [95% confidence interval: 1.12-3.13]; P = 0.018). Five-year overall survival rates were maintenance: 81.9%, and decrease: 61.7% (hazard ratio: 2.95 [95% confidence interval: 1.37-6.33]; P = 0.006). Multivariable Cox proportional hazards models showed that perioperative maintenance of anaerobic threshold was an independent prognostic indicator for both recurrence-free- and overall survival. Although the mean anaerobic threshold from preoperative to postoperative month 6 decreased in the exercise-not-implemented group, the exercise-implemented group experienced increased anaerobic threshold, on average, at postoperative month 6. The significant prognostic factor affecting postoperative survival for chronic liver injury patients with HCC undergoing hepatectomy was maintenance of anaerobic threshold up to 6 months postoperatively.

Risk Factors for Intracardiac Thrombus During Liver Transplantation.

Intracardiac thrombus (ICT) is an intraoperative complication with high mortality that occurs during orthotopic liver transplantation (OLT). Patients with end-stage liver disease have compromised coagulation pathways, and when combined with stressors of surgery, thrombi can form. However, it is unknown which patients are most likely to develop ICT. We performed a retrospective cohort study of all OLT patients at our hospital from 2010 to 2017 to identify risk factors for ICT. An analysis was performed with conventional bivariate tests and logistic regression. The incidence of ICT during OLT was 4.2% (22/528) with a 45.5% (10/22) mortality. Patients who developed ICT had higher physiologic Model for End-Stage Liver Disease scores at the time of transplant (25.1 versus 32.4; P = 0.004), received grafts from donors with a higher body mass index (28.1 versus 32.2 kg/m2 ; P = 0.007), and had longer intraoperative warm ischemia times (53.1 versus 67.5 minutes; P = 0.001). The odds of developing ICT were significantly lower after administration of intravenous (IV) heparin prior to inferior vena cava (IVC) clamping compared with no administration of heparin (odds ratio, 0.25; 95% confidence interval, 0.08-0.75; P = 0.01). In conclusion, the incidence of ICT at our institution is higher than previously reported, which may be explained by our routine use of transesophageal echocardiography. Although many factors associated with ICT in this study are nonmodifiable, administration of IV heparin prior to IVC cross-clamping is modifiable and was found to be protective. Further studies will be needed to confirm findings and ultimately aid in preventing these lethal events.