Evolution of Liver Transplantation Indications: Expanding Horizons.

Liver transplantation (LT) has significantly transformed the prognosis of patients with end-stage liver disease and hepatocellular carcinoma (HCC). The traditional epidemiology of liver diseases has undergone a remarkable shift in indications for LT, marked by a decline in viral hepatitis and an increase in metabolic dysfunction-associated steatotic liver disease (MASLD), along with expanded indications for HCC. Recent advancements in surgical techniques, organ preservation and post-transplant patients' management have opened new possibilities for LT. Conditions that were historically considered absolute contraindications have emerged as potential new indications, demonstrating promising results in terms of patient survival. While these expanding indications provide newfound hope, the ethical dilemma of organ scarcity persists. Addressing this requires careful consideration and international collaboration to ensure equitable access to LT. Multidisciplinary approaches and ongoing research efforts are crucial to navigate the evolving landscape of LT. This review aims to offer a current overview of the primary emerging indications for LT, focusing on acute-on-chronic liver failure (ACLF), acute alcoholic hepatitis (AH), intrahepatic and perihilar cholangiocarcinoma (i- and p-CCA), colorectal liver metastasis (CRLM), and neuroendocrine tumor (NET) liver metastases.

The role of an integrated referral program for patients with liver disease: A network between hub and spoke centers.

INTRODUCTION: Access to Liver transplantation (LT) can be affected by several barriers, resulting in delayed referral and increased risk of mortality due to complications of the underlying liver disease. AIM: To assess the clinical characteristics and outcomes of patients with acute or chronic liver disease referred using an integrated referral program. MATERIALS AND METHODS: An integrated referral program was developed in 1 October 2017 based on email addresses and a 24/7 telephone availability. All consecutive adult patients with liver disease referred for the first time using this referral program were prospectively collected until 1 October 2021. Characteristics and outcomes of inpatients were compared with a historical cohort of patients referred without using the integrated referral program (1 October 2015-1 October 2017). Patients were further divided according to pre- and post-Covid-19 pandemic. RESULTS: Two hundred eighty-one referred patients were considered. End stage liver disease was the most common underlying condition (79.3%), 50.5% of patients were referred as inpatients and 74.7% were referred for LT evaluation. When inpatient referrals (n = 142) were compared with the historical cohort (n = 86), a significant increase in acute liver injury due to drugs/herbals and supplements was seen (p = 0.01) as well as an increase in End stage liver disease due to alcohol-related liver disease and NASH, although not statistically significant. A significant increase in referrals for evaluation for Trans-jugular intrahepatic portosystemic shunt placement was seen over time (5.6% vs. 1%; p = 0.01) as well as for LT evaluation (84.5% vs. 81%; p = 0.01). Transplant-free survival was similar between the study and control groups (p = 0.3). The Covid-19 pandemic did not affect trends of referrals and patient survival. CONCLUSIONS: The development of an integrated referral program for patients with liver disease can represent the first step to standardize already existing referral networks between hub and spoke centers. Future studies should focus on the timing of referral according to different etiologies to optimize treatment options and outcomes.

Immunosuppression for older liver transplant recipients.

Older liver transplant recipients have a lower risk of acute rejection than younger patients (9% for patients aged ≥65 years versus 23% for those aged 18-34 years) and are more vulnerable to immunosuppression-related complications. The number of liver transplant recipients ≥65 years has risen to 22% in Europe and the US, but limited information is available on the optimal immunosuppressive regimen for these patients. In this review, we discuss the appropriate management of immunosuppressive agents in older adults to minimize adverse events while avoiding acute rejection. The way the body processes drugs greatly depends on age. In the case of calcineurin inhibitor drugs, aging reduces hepatic metabolism, leading to changes in their pharmacokinetics. Corticosteroids also show decreased clearance as the patient ages. In severe cases of hypoalbuminemia, dose adjustment of mycophenolate acid derivatives may be necessary. However, the pharmacokinetic profiles of the mammalian target of rapamycin inhibitors, basiliximab, and rabbit anti-thymocyte globulin remain unaffected by age. Furthermore, age-related frailty may impact drug metabolism and require tailored interventions and closer follow-up. Although there is limited research, elderly liver transplant recipients require less immunosuppression with double or triple-agent regimens, lower exposure to calcineurin inhibitors, and a shorter course of corticosteroids. The usage of mammalian target of rapamycin inhibitors in older transplant populations has not been specifically investigated, and thus their usage should align with indications for younger patient groups.

COVID-19 Acute Respiratory Distress Syndrome: Treatment with Helmet CPAP in Respiratory Intermediate Care Unit by Pulmonologists in the Three Italian Pandemic Waves.

COVID-19 Acute Respiratory Distress Syndrome (CARDS) is the most serious complication of COVID-19. The SARS-CoV-2 outbreaks rapidly saturated intensive care unit (ICU), forcing the application of non-invasive respiratory support (NIRS) in respiratory intermediate care unit (RICU). The primary aim of this study is to compare the patients' clinical characteristics and outcomes (Helmet-Continuous Positive Airway Pressure (H-CPAP) success/failure and survival/death). The secondary aim is to evaluate and detect the main predictors of H-CPAP success and survival/death. A total of 515 patients were enrolled in our observational prospective study based on CARDS developed in RICU during the three Italian pandemic waves. All selected patients were treated with H-CPAP. The worst ratio of arterial partial pressure of oxygen (PaO2) and fraction of inspired oxygen (FiO2) PaO2/FiO2 during H-CPAP stratified the subjects into mild, moderate and severe CARDS. H-CPAP success has increased during the three waves (62%, 69% and 77%, respectively) and the mortality rate has decreased (28%, 21% and 13%). H-CPAP success/failure and survival/death were related to the PaO2/FiO2 (worst score) ratio in H-CPAP and to steroids' administration. D-dimer at admission, FiO2 and positive end expiratory pressure (PEEP) were also associated with H-CPAP success. Our study suggests good outcomes with H-CPAP in CARDS in RICU. A widespread use of steroids could play a role.

Advances and Controversies in Acute Alcohol-Related Hepatitis: From Medical Therapy to Liver Transplantation.

Alcohol-related hepatitis (AH) is a clinical syndrome characterized by recent-onset jaundice in the context of alcohol consumption. In patients with severe AH "unresponsive" to steroid therapy, mortality rates exceed 70% within six months. According to European and American guidelines, liver transplantation (LT) may be considered in highly selected patients who do not respond to medical therapy. The aim of this narrative review is to summarize current knowledge from medical therapy to liver transplantation in acute alcohol-related hepatitis. Due to the impossibility to guarantee six-month abstinence, LT for AH is controversial. Principal concerns are related to organ scarcity in the subset of stigma of "alcohol use disorder" (AUD) and the risk of relapse to alcohol use after LT. Return to alcohol use after LT is a complex issue that cannot be assessed as a yes/no variable with heterogeneous results among studies. In conclusion, present data indicate that well-selected patients have excellent outcomes, with survival rates of up to 100% at 24 and 36 months after LT. Behavioral therapy, ongoing psychological support, and strong family support seem essential to improve long-term outcomes after LT and reduce the risk in relapse of alcohol use.

Influence of sex in alcohol-related liver disease: Pre-clinical and clinical settings.

Alcohol-related liver disease (ArLD) is a major cause of chronic liver disease globally. Traditionally, ArLD was mostly a concern in men rather than in women; however, such a sex gap is rapidly narrowing due to increasing chronic alcohol consumption among women. Female sex is more vulnerable to the harmful effects of alcohol with a higher risk of progression to cirrhosis and development of associated complications. The relative risk of cirrhosis and liver-related mortality is significantly higher in women than in men. Our review endeavors to summarize the current knowledge on sex differences in alcohol metabolism, pathogenesis of ArLD, disease progression, indication for liver transplant and pharmacological treatments of ArLD, and provide evidence in support of a sex-specific management of these patients.

Liver transplantation for non-alcoholic fatty liver disease: indications and post-transplant management.

Non-alcoholic fatty liver disease (NAFLD) is currently the fastest growing indication to liver transplantation (LT) in Western Countries, both for end stage liver disease and hepatocellular carcinoma. NAFLD/non-alcoholic steatohepatitis (NASH) is often expression of a systemic metabolic syndrome; therefore, NAFLD/NASH patients require a multidisciplinary approach for a proper pre-surgical evaluation, which is important to achieve a post-transplant outcome comparable to that of other indications to LT. NAFLD/NASH patients are also at higher risk of post-transplant cardiovascular events, diabetes, dyslipidemia, obesity, renal impairment and recurrent NASH. Lifestyle modifications, included diet and physical activity, are key to improve survival and quality of life after transplantation. A tailored immunosuppressive regimen may be proposed in selected patients. Development of new drugs for the treatment of recurrent NASH is awaited.

Topical Steroids and Glaucoma Filtration Surgery Outcomes: An In Vivo Confocal Study of the Conjunctiva.

(1) Background: The purpose of this study is to investigate the effects of topical steroids on conjunctiva in patients undergoing filtration surgery (FS) for glaucoma by using confocal microscopy (CM); (2) Methods: One hundred and four glaucomatous patients were randomized to fluorometholone or lubricants four weeks before FS. CM was performed before treatments and pre-operatively. Dendritic and goblet cell densities (DCD, GCD), stromal meshwork reflectivity (SMR), vascular tortuosity (VT), and intra-ocular pressure (IOP) were the main outcomes. By evaluating treatments and outcomes (12-month success/failure) as categorical variables, patients were grouped into Group 1, 2, 3, or 4 (success/failure with fluorometholone, or lubricants); (3) Results: Twelve-month IOP was reduced in Groups 1 and 3 (p < 0.001). After treatments, DCD and SMR were reduced in Groups 1 and 2 (p < 0.01), and 1 and 3 (p < 0.05), respectively. Pre-operative DCD was lower in the steroid compared to lubricant group (p < 0.001), whereas SMR was lower in successful (1 and 3) compared to failed groups (2 and 4) (p = 0.004). There were no significant differences between the fluorometholone and lubricant groups for success percentages. The number of bleb management procedures and IOP lowering medications were lower in Group 1 compared to Groups 2−4 (p < 0.05); (4) Conclusions: Topical steroids mitigate conjunctival inflammation and lower the stromal density in patients undergoing FS. These modifications lead to less intensive post-operative management.

Coronary artery calcium on standard chest computed tomography predicts cardiovascular events after liver transplantation.

AIMS: Cardiac complications are a leading cause of mortality after orthotopic liver transplantation (LT) and pre-operative risk stratification is challenging. We evaluated whether coronary artery calcium (CAC) score calculated on a standard (non-thin layer, non-ECG gated) chest computed tomography (CT) predicted cardiac outcome after LT. METHODS: We included a consecutive series of LT recipients who underwent pre-operative cardiac evaluation including stress-testing or cardiac catheterization in high-risk patients. Patients with a history of coronary artery disease or coronary revascularization were excluded. The CAC score was calculated from the chest CT routinely performed before LT. CAC values were not available at the time of pre-transplant cardiac evaluation and did not affect LT eligibility. The primary end-point included peri-operative arrhythmic cardiac arrest and sustained ventricular arrhythmias; heart failure, myocardial infarction and cardiac death within 1-year after LT. RESULTS: The study population consisted of 301 patients (median age 56 years, 76% males). At chest CT, 49% had CAC = 0; 27% had CAC = 1-99, 15% had CAC = 100-399 and 9% CAC > 400. The primary end-point incidence increased from 7% in patients with CAC = 0 to 27% in patients with CAC > 400 (p = 0.007). At multivariable analysis including traditional risk factors, CAC remained an independent predictor of cardiac events (p = 0.01). CONCLUSIONS: CAC score calculated on a standard chest CT stratified the risk of cardiac events in patients who underwent LT after negative pre-transplant cardiac evaluation. These findings suggest that evaluation of CAC from a standard chest CT performed for other reasons can be used as an early cardiac risk stratification tool before LT.

Hepatocellular carcinoma and the risk of de novo malignancies after liver transplantation - a multicenter cohort study.

Patients with hepatocellular carcinoma (HCC) are at high risk of second primary malignancies. As HCC has become the leading indication of liver transplant (LT), the aim of this study was to investigate whether the presence of HCC before LT could influence the onset of de novo malignancies (DNM). A cohort study was conducted on 2653 LT recipients. Hazard ratios (HR) of DNM development for patients transplanted for HCC (HCC patients) were compared with those of patients without any previous malignancy (non-HCC patients). All models were adjusted for sex, age, calendar year at transplant, and liver disease etiology. Throughout 17 903 person-years, 6.6% of HCC patients and 7.4% of non-HCC patients developed DNM (202 cases). The median time from LT to first DNM diagnosis was shorter for solid tumors in HCC patients (2.7 vs 4.5 years for HCC and non-HCC patients, respectively, P < 0.01). HCC patients were at a higher risk of bladder cancer and skin melanoma. There were no differences in cumulative DNM-specific mortality by HCC status. This study suggests that primary HCC could be a risk factor for DNM in LT recipients, allowing for risk stratification and screening individualization.

A comprehensive approach to lung function in bronchiectasis.

BACKGROUND: International guidelines recommend simple spirometry for bronchiectasis patients. However, pulmonary pathophysiology of bronchiectasis is very complex and still poorly understood. Our objective was to characterize lung function in bronchiectasis and identify specific functional sub-groups. METHODS: This was a multicenter, prospective, observational study enrolling consecutive adults with bronchiectasis during stable sate. Patients underwent body-plethysmography before and after acute bronchodilation testing, diffusing lung capacity (DLCO) with a 3-year follow up. Air trapping and hyperinflation were a residual volume (RV) > 120%predicted and a total lung capacity>120%predicted. Acute reversibility was: ΔFEV1 ≥12% and 200 mL from baseline (FEV1rev) and ΔRV ≥10% reduction from baseline (RVrev). Sensitivity analyses included different reversibility cutoffs and excluded patients with concomitant asthma or chronic obstructive pulmonary disease. RESULTS: 187 patients were enrolled (median age: 68 years; 29.4% males). Pathophysiological abnormalities often overlapped and were distributed as follows: air trapping (70.2%), impaired DLCO (55.7%), airflow obstruction (41.1%), hyperinflation (15.7%) and restriction (8.0%). 9.7% of patients had normal lung function. RVrev (17.6%) was more frequent than FEV1rev (4.3%). Similar proportions were found after multiple sensitivity analyses. Compared with non-reversible patients, patients with RVrev had more severe obstruction (mean(SD) FEV1%pred: 83.0% (24.4) vs 68.9% (26.2); P = 0.02) and air trapping (RV%pred, 151.9% (26.6) vs 166.2% (39.9); P = 0.028). CONCLUSIONS: Spirometry alone does not encompass the variety of pathophysiological characteristics in bronchiectasis. Air trapping and diffusion impairment, not airflow obstruction, represent the most common functional abnormalities. RVrev is related to worse lung function and might be considered in bronchiectasis' workup and for patients' functional stratification.

Preliminary evaluation of the safety and efficacy of standard intravenous immunoglobulins in pregnant women with primary cytomegalovirus infection.

Hyperimmune globulins were reported to prevent and treat fetal cytomegalovirus (CMV) infection during pregnancy. Here, we report that infusions of standard human intravenous immunoglobulin significantly increase CMV IgG titers and avidity indexes in pregnant women, paving the way to their use for passive transfer of maternal CMV humoral immunity to fetuses. Preliminary data on perinatal outcomes of the first 67 newborns are encouraging.

The inner jet of an active galactic nucleus as revealed by a radio-to-gamma-ray outburst.

Blazars are the most extreme active galactic nuclei. They possess oppositely directed plasma jets emanating at near light speeds from accreting supermassive black holes. According to theoretical models, such jets are propelled by magnetic fields twisted by differential rotation of the black hole's accretion disk or inertial-frame-dragging ergosphere. The flow velocity increases outward along the jet in an acceleration and collimation zone containing a coiled magnetic field. Detailed observations of outbursts of electromagnetic radiation, for which blazars are famous, can potentially probe the zone. It has hitherto not been possible to either specify the location of the outbursts or verify the general picture of jet formation. Here we report sequences of high-resolution radio images and optical polarization measurements of the blazar BL Lacertae. The data reveal a bright feature in the jet that causes a double flare of radiation from optical frequencies to TeV gamma-ray energies, as well as a delayed outburst at radio wavelengths. We conclude that the event starts in a region with a helical magnetic field that we identify with the acceleration and collimation zone predicted by the theories. The feature brightens again when it crosses a standing shock wave corresponding to the bright 'core' seen on the images.