Liver transplantation in hepatocellular carcinoma - should we perform downstaging?

AIM: To compare the long-term outcomes between liver transplant (LT) recipients with hepatocellular carcinoma (HCC) who were downstaged with transarterial-chemoembolization (TACE) to the Milan criteria (MC) and those initially meeting the MC. METHODS: This retrospective study enrolled 198 patients with HCC: 38 were downstaged and 160 patients initially met the MC. Post-LT survival and HCC recurrence-free survival were evaluated. We assessed the association of death and HCC recurrence with TACE, baseline (age, sex, disease etiology, Model of End-stage Liver Disease, tumor number and the sum of maximum tumor diameters, waiting time, alpha-fetoprotein level) and explant characteristics (tumor number and the sum of maximum tumor diameters, micro- and macrovascular invasion). RESULTS: The recipient survival rates one, three, and five years after LT were 88.2%, 80.1%, and 75.9%, respectively. HCC recurrence-free probabilities were 92.3%, 87.9%, and 85%, respectively. The outcomes were comparable between the groups. In multivariate analysis, the number of tumors on the explant, age, and tumor recurrence were independent risk factors for death. Only the sum of maximum tumor diameters on the explant was an independent risk factor for HCC recurrence. CONCLUSIONS: Patients successfully downstaged with TACE to the MC can achieve post-LT recipient and HCC recurrence-free survival comparable with patients initially within the MC. Good response to TACE as a criterion for LT may be a method of selecting patients with favorable biological characteristics.

Liver transplantation in patients with neuroendocrine tumors: a case series and literature review.

Neuroendocrine tumors (NET) are a rare and heterogeneous group of neoplasms with variable biological behavior. They frequently metastasize to the liver, requiring active, multimodality treatment. Surgical resection, possible in only a minority of cases, was until recently the only potentially curative option. For unresectable NET with liver metastases, liver transplantation (LT) emerged as a potential curative treatment due to relatively slow growth and indolent behavior of the metastases. In this case series with literature review, we retrospectively analyzed the characteristics of 12 highly selected patients with metastatic NET disease as an indication for LT treated in our center. We also summarized the proposed prognostic factors, and evaluated and compared the existing selection criteria. The main poor prognostic factors in our patients were high grade NET and primary tumor in the pancreas. Inconsistent liver transplantation outcome parameters make it difficult to standardize patient selection criteria. There is a need for further studies that would fully elucidate the curative potential of LT in patients diagnosed with NET.

Vitamin D for treatment of non-alcoholic fatty liver disease detected by transient elastography: A randomized, double-blind, placebo-controlled trial.

AIM: To evaluate the effects of vitamin D on transient elastography (TE, FibroScan) indices of liver steatosis (controlled attenuation parameter [CAP]) and fibrosis (liver stiffness measurement [LSM]) in adults with non-alcoholic fatty liver disease (NAFLD). PATIENTS AND METHODS: In this randomized (2:1), double-blind, single-centre, 12-month trial, patients with NAFLD were treated with vitamin D (1000 IU/day) (n = 201) or a matching placebo (n = 110). Two co-primary outcomes were changes in CAP and LSM after 360 days of treatment versus baseline. Two main secondary outcomes were CAP/LSM changes after 180 days of treatment. RESULTS: Both CAP and LSM gradually decreased in vitamin D-treated patients and slightly increased in the placebo arm. Vitamin D was superior to placebo for both primary outcomes (mean differences in CAP and LSM changes (-49.5 dB/m [95% CI -59.5 to -39.4] and -0.72 kPa [95% CI -1.43 to 0.00], respectively) and both secondary outcomes (-22.1 dB/m [-32.1 to -12.1] and -0.89 kPa [-1.61 to -0.17], respectively). Of a number of exploratory outcomes (change at 12 months vs. baseline), vitamin D reduced serum uric acid (-17.9 µmol/L [-30.6 to -5.2]), gamma-glutamyltransferase (-8.9 IU/L [-15.5 to -2.3)] and fasting serum insulin levels (-5.1 pmol/L [-9.3 to -0.8]) as well as the homeostatic model assessment of insulin resistance index (-1.6 [-3.1 to -0.2]) (false discovery rate [5%]-adjusted P-values between .0572 and .0952). CONCLUSION: Low-medium dose supplementation of vitamin D (1000 IU/day) over 12 months reduces TE indices of liver steatosis (CAP) and fibrosis (LSM) in NAFLD patients.

Improved Applicability and Diagnostic Accuracy of the Novel Spleen-Dedicated Transient Elastography Device for High-Risk Esophageal Varices.

Spleen stiffness measurement (SSM) by transient elastography (TE) has been repeatedly demonstrated as the reliable way to rule out the presence of high-risk esophageal varices (HRV). We aimed to evaluate and compare novel vs. standard TE-SSM module performance in diagnosing HRV in patients with compensated advanced chronic liver disease (cACLD). This retrospective study included patients with cACLD; blood data, upper digestive endoscopy performed within 3 months of TE, SSM@50Hz and SSM@100Hz were collected. Overall, 112 patients with cACLD were analyzed (75.9% males, average age of 66, 43.7% alcohol-related chronic liver disease, 22.3% metabolic-associated steatotic liver disease, 6.2% viral hepatitis). Reliable SSM was possible in 80.3% and 93.8% of patients by using SSM@50Hz and SSM@100Hz probe, respectively. At the cut-off 41.8 kPa and 40.9 kPa (Youden), SSM@50Hz and SSM@100Hz had AUROCs of 0.746 and 0.752, respectively, for diagnosing HRV (p = 0.71). At the respective cut-offs, sensitivities for HRV were 92.9% and 100%, resulting in misclassification rates of 7.1% and 0% by using SSM@50Hz and SSM@100Hz. SSM reliably excludes HRV in cACLD patients, with measurements below 41 kPa potentially avoiding EGD in around 50% of cases, with minimal risk of HRV omission. SSM@100Hz demonstrated less measurement failures and no HRV misclassification.

Compensated Advanced Chronic Liver Disease and Steatosis in Patients with Type 2 Diabetes as Assessed through Shear Wave Measurements and Attenuation Measurements.

Patients with type 2 diabetes (T2D) are at risk of developing metabolic dysfunction-associated steatotic liver disease (MASLD). We investigated the prevalence of compensated advanced chronic liver disease (cACLD) and steatosis in patients with T2D using the new non-invasive diagnostic methods of shear wave measurements (SWMs) and attenuation (ATT) measurements in comparison with those of vibration-controlled transient elastography (VCTE) and the controlled attenuation parameter (CAP), which served as the reference methods. Among 214 T2D patients, steatosis at any grade and cACLD were revealed in 134 (62.6%) and 19 (8.9%) patients, respectively. SWMs showed a high correlation with VCTE (Spearman's ρ = 0.641), whereas SWMs produced lower (mean of -0.7 kPa) liver stiffness measurements (LSMs) overall. At a LSM of >11.0 kPa (Youden), SWMs had an AUROC of 0.951 that was used to diagnose cACLD (defined as a LSM of >15 kPa through VCTE) with 84.2% sensitivity and 96.4% specificity. The performance of ATT measurements in diagnosing liver steatosis at any grade (defined as the CAP of ≥274 dB/m) was suboptimal (AUROC of 0.744 at the ATT measurement cut-off of >0.63 dB/cm/MHz (Youden) with 59% sensitivity and 81.2% specificity). In conclusion, the prevalence of liver steatosis and previously unrecognized cACLD in patients with T2D is high and SWMs appear to be a reliable diagnostic method for this purpose, whereas further investigation is needed to optimize the diagnostic performance of ATT measurements.

The Burden of Hepatitis E Infection in Chronic Liver Diseases in Croatia.

In patients with chronic liver disease (CLD), hepatitis E virus (HEV) may lead to decompensation and death. We tested 438 CLD patients (71.0% male; age 23-84 years) for HEV-IgG antibodies. Reactive samples were tested for HEV-IgM antibodies using ELISA. IgM positive samples were tested for HEV RNA using RT-PCR. HEV-IgG antibodies were found in 15.1% of patients, whereas 4.5% of IgG positive patients had detectable IgM antibodies. Not a single patient tested HEV RNA positive. Seroprevalence increased with age, from 9.7% (<45 years) to 17.4% (>60 years, p = 0.368). There was no difference in HEV-IgG seropositivity related to gender, level of education, geographic region, area of residence, liver disease, or hepatocellular carcinoma presence. Previous exposure to HEV was detected in 15.1% of patients, corresponding with the data from other endemic European regions. Despite the high local exposure, we did not find any evidence of acute or chronic hepatitis E among CLD patients.

West Nile Virus: An Emerging Threat in Transplant Population.

West Nile virus (WNV) has become one of the new challenges for transplant programs. In addition to transmission by mosquito bite, interhuman transmission is possible through blood products or organ transplantation. Majority of WNV infections present as asymptomatic or mild febrile illness, with less than 1% of infected developing neuroinvasive disease. Many studies report naturally acquired or donor-derived WNV infections in solid-organ transplant recipients, mainly kidney, but also liver, heart, lungs and pancreas. Given the much higher risk of neuroinvasive disease (40% and even higher) based on serologic and clinical studies and increased mortality in transplant population, WNV infection should be considered in all patients presented with fever and neurological symptoms after transplantation, especially during the arbovirus transmission season.

Seroepidemiology of hepatitis E in patients on haemodialysis in Croatia.

PURPOSE: Data on the seroprevalence of hepatitis E virus (HEV) in heamodialysis (HD) patients are conflicting, ranging from 0 to 44%. The aim of this study was to determine the HEV seroprevalence and risk factors among HD patients in Croatia. METHODS: A total of 394 HD patients from six medical facilities in five Croatian cities (three sites in the continental and three sites in the coastal region) were tested for HEV IgM/IgG antibodies using an enzyme-linked immunosorbent assay. Additionally, all samples were tested for HEV RNA by RT-PCR. Sociodemographic data and risk factors were collected using a questionnaire. RESULTS: HEV IgG antibodies were detected in 110 (27.9%) patients. The seroprevalence varied significantly between dialysis centres, ranging from 5.2 to 43.4% (p = 0.001). HEV IgM antibodies were found in 0.04% of IgG positive patients. All patients tested negative for HEV RNA. Factors associated with HEV IgG seropositivity were age > 60 years (OR 8.17; 95% CI 1.08-62.14), living in the continental parts of the country (OR 2.58; 95% CI 1.55-4.30), and transfusion of blood products (OR 1.66; 95% CI 1.01-2.73). After adjusting for age and gender, patients from continental regions had higher odds of HEV seropositivity compared to patients from coastal regions (OR 2.88; 95% CI 1.71-4.85) and those who had RBC transfusions (OR 1.70, 95% CI 1.02-2.69) compared to those who did not. CONCLUSION: The study showed a high HEV seropositivity among HD patients in Croatia, with significant variations between geographical regions. Continental area of residence and RBC transfusion were the most significant risk factors for HEV seropositivity. Due to the high seroprevalence, routine HEV screening among HD patients, especially in transplant candidates should be considered.

Hepatitis E seroprevalence and associated risk factors in Croatian liver transplant recipients.

INTRODUCTION: Solid-organ transplant recipients are at risk of hepatitis E virus (HEV) infection. We analyzed the seroprevalence/risk factors of HEV in Croatian liver transplant recipients. METHODS: Two hundred forty-two serum samples were tested for HEV immunoglobuline IgG/IgM and HEV RNA. Sociodemographic data and risk factors were collected using a questionnaire. RESULTS: HEV IgG seroprevalence rate was 24.4%. Positive/equivocal HEV IgM were found in two patients. HEV RNA was not detected. Logistic regression showed that older age, female gender, rural area/farm, water well, and septic tank were associated with HEV seropositivity. CONCLUSIONS: This study revealed a high exposure rate to HEV in Croatian liver recipients.

Epidemiology of hepatitis E in South-East Europe in the "One Health" concept.

The significance of hepatitis E virus (HEV) as an important public health problem is rising. Until a decade ago, cases of HEV infection in Eur-ope were mainly confined to returning travelers, but nowadays, hepatitis E represents an emerging zoonotic infection in many European countries. The aim of this manuscript is to perform a systematic review of the published literature on hepatitis E distribution in humans, animals and environmental samples ("One Health" concept) in the South-Eastern European countries. Comparison of the available data showed that the anti-HEV seroprevalence in the South-Eastern Europe varies greatly, depending on the population studied, geographical area and methods used. The IgG seroprevalence rates in different population groups were found to be 1.1%-24.5% in Croatia, up to 20.9% in Bulgaria, 5.9-%17.1% in Romania, 15% in Serbia, up to 9.7% in Greece and 2%-9.7% in Albania. Among possible risk factors, older age was the most significant predictor for HEV seropositivity in most studies. Higher seroprevalence rates were found in animals. HEV IgG antibodies in domestic pigs were detected in 20%-54.5%, 29.2%-50%, 38.94%-50% and 31.1%-91.7% in Serbia, Bulgaria, Romania and Croatia, respectively. In wild boars seroprevalence rates were up to 10.3%, 30.3% and 31.1% in Romania, Slovenia and Croatia, respectively. A high HEV RNA prevalence in wild boars in some countries (Croatia and Romania) indicated that wild boars may have a key role in the HEV epidemiology. There are very few data on HEV prevalence in environmental samples. HEV RNA was detected in 3.3% and 16.7% surface waters in Slovenia and Serbia, respectively. There is no evidence of HEV RNA in sewage systems in this region. The available data on genetic characterization show that human, animal and environmental HEV strains mainly belong to the genotype 3.

Emerging Trends in the Epidemiology of West Nile and Usutu Virus Infections in Southern Europe.

The epidemiology of West Nile (WNV) and Usutu virus (USUV) has changed dramatically over the past two decades. Since 1999, there have been regular reports of WNV outbreaks and the virus has expanded its area of circulation in many Southern European countries. After emerging in Italy in 1996, USUV has spread to other countries causing mortality in several bird species. In 2009, USUV seroconversion in horses was reported in Italy. Co-circulation of both viruses was detected in humans, horses and birds. The main vector of WNV and USUV in Europe is Culex pipiens, however, both viruses were found in native Culex mosquito species (Cx. modestus, Cx. perexiguus). Experimental competence to transmit the WNV was also proven for native and invasive mosquitoes of Aedes and Culex genera (Ae. albopictus, Ae. detritus, Cx. torrentium). Recently, Ae. albopictus and Ae. japonicus naturally-infected with USUV were reported. While neuroinvasive human WNV infections are well-documented, USUV infections are sporadically detected. However, there is increasing evidence of a role of USUV in human disease. Seroepidemiological studies showed that USUV circulation is more common than WNV in some endemic regions. Recent data showed that WNV strains detected in humans, horses, birds, and mosquitoes mainly belong to lineage 2. In addition to European USUV lineages, some reports indicate the presence of African USUV lineages as well. The trends in WNV/USUV range and vector expansion are likely to continue in future years. This mini-review provides an update on the epidemiology of WNV and USUV infections in Southern Europe within a multidisciplinary "One Health" context.

Hepatitis E seroprevalence and associated risk factors in Croatian liver transplant recipients

Abstract INTRODUCTION Solid-organ transplant recipients are at risk of hepatitis E virus (HEV) infection. We analyzed the seroprevalence/risk factors of HEV in Croatian liver transplant recipients. METHODS Two hundred forty-two serum samples were tested for HEV immunoglobuline IgG/IgM and HEV RNA. Sociodemographic data and risk factors were collected using a questionnaire. RESULTS HEV IgG seroprevalence rate was 24.4%. Positive/equivocal HEV IgM were found in two patients. HEV RNA was not detected. Logistic regression showed that older age, female gender, rural area/farm, water well, and septic tank were associated with HEV seropositivity. CONCLUSIONS This study revealed a high exposure rate to HEV in Croatian liver recipients.