Recurrence of hepatocellular carcinoma after liver transplantation: Prognostic and predictive factors of survival in a Latin American cohort.

BACKGROUND & AIM: Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) has a poor prognosis, and the adjusted effect of different treatments on post-recurrence survival (PRS) has not been well defined. This study aims to evaluate prognostic and predictive variables associated with PRS. METHODS: This Latin American multicenter retrospective cohort study included HCC patients who underwent LT between the years 2005-2018. We evaluated the effect of baseline characteristics at time of HCC recurrence diagnosis and PRS (Cox regression analysis). Early recurrences were those occurring within 12 months of LT. To evaluate the adjusted treatment effect for HCC recurrence, a propensity score matching analysis was performed to assess the probability of having received any specific treatment for recurrence. RESULTS: From a total of 1085 transplanted HCC patients, the cumulative incidence of recurrence was 16.6% (CI 13.5-20.3), with median time to recurrence of 13.0 months (IQR 6.0-26.0). Factors independently associated with PRS were early recurrence (47.6%), treatment with sorafenib and surgery/trans-arterial chemoembolization (TACE). Patients who underwent any treatment presented "early recurrences" less frequently, and more extrahepatic metastasis. This unbalanced distribution was included in the propensity score matching, with correct calibration and discrimination (receiving operator curve of 0.81 [CI 0.72;0.88]). After matching, the adjusted effect on PRS for any treatment was HR of 0.2 (0.10;0.33); P < .0001, for sorafenib therapy HR of 0.4 (0.27;0.77); P = .003, and for surgery/TACE HR of 0.4 (0.18;0.78); P = .009. CONCLUSION: Although early recurrence was associated with worse outcome, even in this population, systemic or locoregional treatments were associated with better PRS.

Impact of Brazilian expanded criteria for liver transplantation in patients with hepatocellular carcinoma: a multicenter study.

INTRODUCTION AND OBJECTIVES: Hepatocellular carcinoma (HCC) is one of the main indications for orthotopic liver transplantation (OLT). In Brazil, selection criteria for HCC is an expanded version of the Milan Criteria (MC), the so-called "Brazilian Milan Criteria" (BMC). Our aims were to evaluate post-OLT outcomes in patients with HCC and analyze the BMC performance. MATERIALS AND METHODS: We conducted a multicenter, retrospective cohort study, analyzing medical records of 1,059 liver transplant recipients with HCC. Tumor was staged according to MC and BMC and correlated with overall survival (OS) and disease-free survival (DFS). We compared the ability of MC and BMC to predict OS and DFS using Delta C-statistic. RESULTS: Post-OLT OS were 63% in five years and HCC recurrence was observed in 8% of patients. At diagnosis, 85% of patients were within MC. Patients within MC at diagnosis and in the explant showed a higher OS and DFS than patients outside MC and within BMC and patients outside both criteria (p < 0.001). Patients outside MC in the explant had an increased risk of tumor recurrence (HR: 3.78; p < 0.001) and poor survival (HR:1.77; p = 0.003). The BMC presented a lower performance than MC in properly classifying patients regarding recurrence risk. CONCLUSIONS: In a large Brazilian cohort of HCC patients submitted to liver transplantation, we observed satisfactory overall survival and recurrence rates. However, patients transplanted within the Brazilian expanded criteria had lower OS and DFS when compared to patients within MC, which may generate future discussions regarding the criteria currently used.

Circulating levels of High-mobility group box 1 protein and nucleosomes are associated with outcomes after liver transplant.

BACKGROUND: Liver transplantation (LT) can be associated with early complications, such as allograft dysfunction and acute kidney injury, which contribute significantly to morbidity and mortality. High-mobility group box 1 protein (HMGB1) has been identified as mediator in ischemia-reperfusion injury. Nucleosomes are complexes formed by DNA and histone proteins, and histones contribute to organs failure and death during sepsis. METHODS: HMGB1 and nucleosome plasma levels were measured, by enzyme-linked immunosorbent assays, during LT and in the first 48 post-operative hours in 22 LT patients. The association between HMGB1 and nucleosome levels and the complications and survival within 6 months after LT were investigated. RESULTS: We observed peak HMGB1 and nucleosome levels after graft reperfusion. HMGB1 and nucleosome levels were associated with the occurrence of acute kidney injury, early allograft dysfunction, and early survival after LT. Nucleosome levels after graft reperfusion were associated with the occurrence of systemic inflammatory response syndrome. CONCLUSIONS: HMGB1 and nucleosome levels increased after liver reperfusion in human LT setting and were associated with early complications and survival. New studies are necessary to explore their role as early markers of hepatocellular injury in human LT and the risk of graft and organs dysfunction and death.

Prospective evaluation of metabolic syndrome and its components among long-term liver recipients.

BACKGROUND & AIMS: Survival after liver transplantation (LTx) has increased. Metabolic syndrome (MS) is widely reported in patients in the early years after LTx; few studies have researched this condition in relatively long-term liver recipients. To describe, prospectively, the prevalence of MS, its components and its associated factors in relatively long-term liver recipients. METHODS: A total of 117 patients were evaluated in 2008 (median of 3 years after LTx, range 0-13 years) and in 2012 (median of 7 years after LTx, range 3-17 years) for the presence of MS [using modified NCEP Adult Treatment Panel III and International Diabetes Federation (IDF) criteria]; its components; and its associated factors, including demographic, socioeconomic, lifestyle, clinical, body composition (measured using bioelectric impedance) and dietetic factors. RESULTS: MS increased over the years (IDF, 43.1-53.3%, P=0.12; and NCEP, 34.3-44.8%, P=0.03). Blood glucose increased over the years (98.8±24.7 to 109.2±33.3 mg/dl, P<0.01), which resulted in an increased prevalence of glucose intolerance (34.2-48.6%, P<0.01). Waist circumference (93.3±14.3 to 99.4±14.9 cm, P<0.01) and body fat (30.3±8.9 to 31.8±10.3%, P=0.03) also increased. The MS associated factors (P<0.05) were age [Odds ratio (OR) 1.05, confidence interval (CI) 1.02-1.11], family history of diabetes (OR 3.38, CI 1.19-9.61), body mass index (BMI) prior to liver disease (OR 1.39, CI 1.19-1.63) and body fat (OR 1.09, CI 1.03-1.14). The MS components were associated (P<0.05) with greater age, family history of diabetes, current and previous BMI, body fat, current corticosteroid use, lack of exercise and greater carbohydrate and fat intakes. CONCLUSION: MS prevalence increased over the years after LTx because of the increases in waist circumference and blood glucose. MS and its components are associated with modifiable factors, such as greater BMI, body fat and carbohydrate and fat intake.

Cd34 Immunostaining Adds Specificity To Microvascular invasion Analysis in Hepatocellular Carcinoma.

Introduction: Hepatocellular carcinoma is the most common primary neoplasia of the liver. Microvascular invasion predicts outcome and defines tumor staging. However, its diagnosis is still a challenge. The present study aims to evaluate inter and intraobserver agreement in identifying the presence of microvascular invasion using conventional and immunohistochemistry histology. Methods: Three pathologists performed the analysis of 76 hepatocellular carcinoma explants to characterize the presence of microvascular invasion using the hematoxylin/eosin stain and immunohistochemistry for CD34. The evaluations were made individually, in two distinct moments. Results were analyzed by the Kappa's coefficient and ROC curves. Results: Our study demonstrated similar agreement for microvascular invasion between hematoxylin/eosin and CD34 methods. However, the intraobserver agreement values for both methods were higher than the interobserver ones. The accuracy of CD34 in relation to hematoxylin/eosin by ROC curves in intraobserver analysis tends to a high specificity, ranging from 82.1 to almost 100%, with sensitivity of 46.9% to 81.1%. In interobserver analysis, CD34 also has a high specificity (84.3% to 85.5%) while its sensitivity is a little shorter (81.2% to 84.3%). Conclusion: Intraobserver higher agreement allows us to suppose that pathologists employed own criteria to evaluate vascular invasion, reinforcing the need of standardization. ROC Curves analysis showed that the CD34 method is more specific than sensitive. Therefore, immunohistochemistry for CD34 should not be used routinely, but it could be useful to help confirming invasion previously seen by conventional histology.

Assessment of nutritional status of patients waiting for liver transplantation.

Patients with advanced liver disease have several risk factors to develop nutritional deficiencies. Accurate nutritional assessment is a real challenge because many of the traditionally measured parameters of nutritional status vary with severity of liver disease independently of nutritional status. The objective of this study was to compare different tools used to assess the nutritional status of patients waiting for a liver transplant. Patients were nutritionally assessed by SGA, anthropometry, handgrip dynamometry and biochemical tests. Clinical variables were cross analyzed with the nutritional assessment methods. There were 159 patients followed. Malnutrition ranged from 6.3% to 80.8% according to the different methods used. Agreement among all the methods was low (K < 0.26). Malnutrition prevalence according to different nutritional assessment tools did not differ among this group of patients in relation to the etiology of liver disease (p > 0.05) but increased with the more advanced stages of disease according to the Child-Pugh score. Only SGA showed significant relationships with clinical variables (Child-Pugh scores, p < 0.05; presence of ascites and/or edema, p < 0.01; and encephalopathy, p < 0.01). The various methods used showed great variability of results, lack agreement among them, and only SGA showed correlation with the progression of liver disease.

Donor-Derived Tuberculosis: A Case Report and the Role of Communication Gaps in Transplantation Safety.

Donor-derived tuberculosis (DD-TB) accounts for less than 5% of TB cases and is considered a rare event. In the transplant setting, the frequency of active TB is estimated to be 20 to 74 times higher than that in the general population, and it is associated with high mortality. In this context, the main strategy to minimize the risk of DD transmission is to identify high-risk donors. Despite screening recommendations, failures may result in a breakdown of safety that ends in the transmission of potentially fatal diseases. This report describes a case of DD-TB and emphasizes communication gaps that may occur between organ procurement organizations and transplant centers. Failure in reporting results, lack of exchanging information regarding recipients from the same donor, and inefficient communication between organ procurement organizations and transplant centers are lacks that may be prevented by a more efficient approach towards screening protocols and communication.

Hepatocellular carcinoma recurrence after liver transplantation in a Brazilian multicenter study: clinical profile and prognostic factors of survival.

BACKGROUND: Liver transplantation (LT) is the treatment of choice for patients with unresectable early hepatocellular carcinoma (HCC). Post-LT HCC recurrence rates range from 8 to 20% and still impact on overall survival (OS). The aim of our study was to evaluate the impact of HCC recurrence on post-LT survival and analyze prognostic factors among those patients with recurrence. PATIENTS AND METHODS: We carried out a national, multicenter, retrospective cohort study in Brazil. Medical records of 1119 LT recipients with HCC were collected. Data from patients with post-LT HCC recurrence were analyzed and correlated with post-relapse survival. RESULTS: OS of the 1119 patients included in the study was 63% over 5 years. Post-LT HCC recurrence occurred in 86 (8%) patients. The mean time to recurrence was 12 months. Sites of recurrence were extrahepatic in 55%, hepatic in 27%, and both hepatic and extrahepatic in 18%. Recurrence treatment was performed in 50 (64%) cases, mostly with sorafenib. Post-relapse survival rates were 34% at 1 year and 13% at 5 years. Univariable analysis identified α-fetoprotein more than 1000 ng/ml at relapse, recurrence treatment, extrahepatic location, and time to recurrence more than 2 years as prognostic factors. In multivariable analysis, recurrence treatment, extrahepatic location, and time to recurrence more than 2 years were independent predictors of better survival. CONCLUSION: In a large Brazilian cohort of LT recipients with HCC, post-LT HCC recurrence occurred in 8% and impacted significantly on the OS. Patients with early recurrence presented a worse prognosis. However, treatment of recurrence improved outcomes, highlighting the importance of early diagnosis.

Energy expenditure and balance among long term liver recipients.

BACKGROUND: Excessive weight gain in patients undergoing liver transplantation has been well documented. The etiology for this complication is not well defined, although it has a high prevalence in post-transplant patients. Reduced energy expenditure may be related to excessive weight gain. Thus, the assessment of the resting energy expenditure (REE) in this patient population is of utmost importance. METHODS: Therefore, patients who underwent liver transplantation had their REEs measured by indirect calorimetry (IC). These results were compared with the demographic, socioeconomic, clinical, anthropometric, dietary and lifestyle variables assessed by uni- and multivariate statistical analyses. The REEs were also compared to estimates using the Harris-Benedict formula, and the patients were classified as hypo-, normo- and hypermetabolic. RESULTS: We evaluated 42 patients with an average of 6.5 years post-transplant and an REE of 1449.7 kcal/day (measured by IC) or 1404.5 kcal/day (predicted by the HB formula). There was great correlation between the methods, and the best predictors of REE were age, weight, amount of lean mass and amount of total body water. Excessive weight was observed in 57% of patients, and obesity was observed in 26.2%. Underreporting of energy intake was observed in 65.8% of patients, and most patients (92.7%) were classified as sedentary or less active. No patient was classified as hypometabolic. CONCLUSIONS: These results indicate that hypometabolism should be discarded as cause of the high prevalence of overweight and obese patients in the population undergoing LT. However, energy consumption and low levels of physical activity may be risk factors.

Resting energy expenditure, body composition, and dietary intake: a longitudinal study before and after liver transplantation.

BACKGROUND: The loss of hepatic innervations after liver transplantation (LTx) might affect the energy metabolism of the patients. The aim of this study was to assess the resting energy expenditure (REE), body composition, and dietary intake before and during the first year after the LTx. METHODS: The REE was measured by indirect calorimetry. Nutritional status was assessed by anthropometric assessment, bioimpedance, handgrip strength, and dietary intake (before and 30, 90, 180, 270, and 370 days after LTx). Social, clinical, and nutritional variables were assessed as being potentially associated with REE or hypermetabolism and hypometabolism after LTx. RESULTS: Seventeen patients were included. REE was elevated at 30 days and reduced at the end of the study (P<0.05). Hypermetabolism/hypometabolism were low but present at the end of the study (11.8% of each). Increases in body weight and fat mass were observed (P<0.05). Handgrip strength and phase angle improved after LTx (P<0.05). Energy balance was positive at all times after LTx, and an increase in fat intake occurred (P<0.05). After multivariate analyses (P<0.05), the REE before transplantation and triceps skinfold thickness were positively associated and the cumulative dose of prednisone was negatively associated with REE after LTx. The presence of hypermetabolism was significantly associated with the presence of hypermetabolism before LTx and the cumulative dose of prednisone. Percentage of fat intake and fat mass before LTx was associated with hypometabolism. CONCLUSION: Some potential modifiable factors are related to resting energy metabolism in patients undergoing LTx. Adequate and individualized nutritional guidance should be started before LTx.

Overweight in liver transplant recipients.

This review aims to describe the incidence and prevalence of overweight and obesity after liver transplantation and the consequences associated with it. Literature review consultation was conducted in Medline / PubMed, SciELO, EMBASE and LILACS, with the combination of the following keywords: liver transplantation, overweight, obesity, weight gain. Overweight is incident on more than 60% of patients undergoing liver transplantation and obesity rates exceed 20% in the first year after surgery, during which occurs the largest relative weight gain. Studies have shown that between 60% and 70% of patients undergoing liver transplantation are overweight after the third year, 90% with abdominal obesity. Associated factors are, among others, advanced age, family history of overweight and excess weight prior to liver disease. The contribution of immunosuppressive medication remains controversial. Some of the consequences of overweight are liver steatosis, steatohepatitis, diabetes mellitus, hypertension, dyslipidemia, cardiovascular disease and death.

Tuberculosis in liver transplant recipients: a single Brazilian center experience.

BACKGROUND: Tuberculosis (TB) is an important opportunistic infection in transplant recipients worldwide. The frequency of Mycobacterium tuberculosis disease varies among different regions, but the incidence of TB in adult liver transplant (LT) recipients is largely unknown. The estimated frequency ranges from 0.7% to 2.3%, with mortality rate up to 30%. However, these data are based on individual case reports or series with small samples. In LT recipients, therapy is generally associated with significant hepatotoxicity and interactions with immunosuppressive drugs. METHODS: This retrospective analysis included 319 patients who underwent LT at University Hospital, Federal University of Minas Gerais, Brazil, between September 1994 and July 2007 and survived more than 1 month. Among these, TB was diagnosed in five patients. No patients received chemoprophylaxis before or after LT. RESULTS: All five patients were women, mean age 39.6+/-16.5 years. Two patients had disseminated TB, two pulmonary involvement, and one extrapulmonary disease. Cultures were positive in four patients. Overall, four patients received isoniazid, rifampin, and pyrazinamide for 6 to 12 months, with good tolerance, but one patient presented recurrence. Another patient presented raised hepatic enzymes levels after initiating therapy. All patients are alive and well. CONCLUSIONS: In this series, the TB frequency after liver transplantation was 1.57%, with no confirmed hepatotoxicity with conventional treatment and an excellent survival rate (100%).

Excesso de peso em pacientes submetidos ao transplante hepático / Overweight in liver transplant recipients

Esta revisão tem por objetivo descrever a incidência e prevalência de excesso de peso, sobrepeso e obesidade pós-transplante hepático e as consequências associadas a ele. Foi realizada revisão bibliográfica com consulta nas bases Medline/Pubmed, SciELO, EMBASE, LILACS com o cruzamento dos seguintes descritores: transplante hepático; sobrepeso; obesidade; ganho de peso. O excesso de peso é incidente em mais de 60% dos pacientes submetidos ao transplante hepático e as taxas de obesidade ultrapassam 20% já no primeiro ano do pós-operatório, período em que ocorre o maior ganho de peso relativo. Estudos revelaram que entre 60% e 70% dos pacientes submetidos ao transplante de fígado apresentam excesso de peso após o terceiro ano e quase 90% deles com obesidade abdominal. Os fatores associados são os mais variados, dentre os quais se destacam maior idade, história familiar de excesso de peso, excesso de peso anterior à doença hepática, dentre outros. A contribuição da medicação imunossupressora ainda permanece controversa. Dentre as consequências do excesso de peso estão a esteatose hepática, esteatohepatite, diabete melito, hipertensão, dislipidemias, doenças cardiovasculares e morte.

This review aims to describe the incidence and prevalence of overweight and obesity after liver transplantation and the consequences associated with it. Literature review consultation was conducted in Medline / PubMed, SciELO, EMBASE and LILACS, with the combination of the following keywords: liver transplantation, overweight, obesity, weight gain. Overweight is incident on more than 60% of patients undergoing liver transplantation and obesity rates exceed 20% in the first year after surgery, during which occurs the largest relative weight gain. Studies have shown that between 60% and 70% of patients undergoing liver transplantation are overweight after the third year, 90% with abdominal obesity. Associated factors are, among others, advanced age, family history of overweight and excess weight prior to liver disease. The contribution of immunosuppressive medication remains controversial. Some of the consequences of overweight are liver steatosis, steatohepatitis, diabetes mellitus, hypertension, dyslipidemia, cardiovascular disease and death.