Frailty and sarcopenia in patients with cirrhosis awaiting liver transplantation: evidence from a single-centre, prospective cohort study.

Sarcopenia and frailty are common complications in patients with cirrhosis evaluated for liver transplantation (LT). Although the negative impact of sarcopenia on patient's outcome has been well studied, the prognostic role of frailty is not as clear. We assessed the prevalence of sarcopenia and frailty and the clinical impact of frailty in a prospective cohort of cirrhosis patients with and without hepatocellular carcinoma (HCC) listed for LT. Patients with cirrhosis were prospectively recruited at the time of admission into the waiting list. Clinical and lab values were collected. Physical frailty was assessed by liver frailty index (LFI) and patients were categorized into robust (< 3.2); pre-frail (between 3.2 and 4.5), and frail (> 4.5). Skeletal muscle mass was evaluated via skeletal muscle index (SMI) obtained from last CT scan before LT; sarcopenia was defined by SMI < 50 cm2/m2 in males and < 39 cm2/m2 in females. 105 patients were included, of which 42 (40%) had hepatocellular carcinoma (HCC). In patients without HCC (63.5% males, median age 61 years), 36.5% were frail, 50.8% were pre-frail and 12.7% were robust. Frail patients were older than non-frail patients (63 vs. 56; p = 0.008) and had more severe liver disease (Child C: 65% vs. 37.5%; p = 0.02). Prevalence of sarcopenia in patients without HCC was 63%, with similar value of median SMI between frail and not frail patients (p = 0.454). Patients with HCC (78.6% males, 65 years old) were 21.4% frail, 61.9% pre-frail, and 16.7% robust. Frail patients had more severe liver disease (Child C: 77% vs. 18.2%; p = 0.004), whereas age was comparable to non-frail patients; among patients without HCC, during a median follow-up of 263 days, 17% died (of which 72% were frail) and 10 patients were delisted due to clinical improvement (none of whom were frail). Among those with HCC, during a median follow-up of 289 days, 4 (9%) patients died of which 50% were frail. Frailty and sarcopenia are common complications in patients with cirrhosis awaiting LT. Frailty appears to be associated with an increased risk of mortality during wait-list time especially in those with decompensated cirrhosis. At univariate analysis Meld score, Child score and presence of frailty were found to be associated with shorter survival, however, at multivariate analysis presence of frailty and Child C vs. A/B were the only independent predictor of death. Larger cohorts are required to confirm these results.

Sex disparities in acute-on-chronic liver failure: From admission to the intensive care unit to liver transplantation.

Acute-on-chronic liver failure (ACLF) is a severe clinical syndrome characterized by acute liver decompensation in patients with chronic liver disease, marked by systemic inflammation and systemic organ failure. In this review, we discussed sex-related disparities in the incidence, prognosis, and access to liver transplantation (LT) for patients with ACLF, particularly during Intensive Care Unit (ICU) management. Some studies have suggested that ACLF is more prevalent among male patients admitted to the ICU, and they have higher mortality rates than females. Available prognostic scores, such as CLIF-C or TAM-score, lack sex-specific adjustments. Sarcopenia seems to enhance the accuracy of these scores though this is observed only in male individuals. LT is the only effective treatment for patients with ACLF grade 2-3 who do not respond to medical therapies. Sex-related disparities occur in both access to LT and post-transplant outcomes, although the influence of sex on the prevalence, clinical course, and listing for LT in ACLF remains largely undetermined. A sex-orientated analysis of ICU outcomes in ACLF would facilitate the development of sex-orientated management strategies, thereby improving patients' outcomes.

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.

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.

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.

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.