[CHALLENGES IN LIVER TRANSPLANT 2023].

INTRODUCTION: Liver transplantation improves the survival and the quality of life of patients with liver failure and primary liver carcinoma. Candidates for liver transplantation are thoroughly evaluated to rule out infectious and malignant conditions that might deteriorate following the immune suppression so that their cardiovascular and pulmonary function can sustain them through the surgical procedure. Poor nutritional status, sarcopenia and frailty portend a poor prognosis before and after the transplantation. Steatohepatitis (NASH) emerges as the most common indication for liver transplantation due to liver cirrhosis and liver tumors. NASH patients are often elderly and have comorbidities such as cardiovascular disease, renal failure and sarcopenia. Particular effort should be invested to ameliorate these conditions in order to minimize waiting list dropout and to improve the outcome after surgery. The Israeli Ministry of Health is responsible for the regulation of organ transplants in Israel - by law. It organizes the procurement and allocation of organs and supervises all the transplant activity. All the candidates are listed on the national waiting list and the priority is allocated according to the MELD-Na. Transplant candidates who carry EDI cards (expressing their advanced directive of consent to organ donation after death) receive additional points on the waiting list. Acute liver failure, hepatopulmonary syndrome and hepatocellular carcinoma patients are prioritized according to their condition, as their MELD score does not reflect their prognosis. To overcome the continuous shortage of organs new techniques have been adopted such as living donor liver transplantation, better management of marginal livers, be they from brain dead donors or donations after circulatory death. The main challenges after liver transplantation are the metabolic syndrome and its complications, renal failure and malignancy. An aggressive, early preventive approach is highly recommended to promote a healthy lifestyle, optimize medical therapy and screen for malignancy.

Barriers and Facilitators of Hepatitis C Care in Persons Coinfected with Human Immunodeficiency Virus.

Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) are often co-transmitted. Viral coinfection results in worse outcomes. Persons who inject drugs (PWIDs) face barriers to medical treatment, but HCV treatment is indicated and effective even with ongoing active drug use. We aimed to assess access to HCV care and treatment results in patients coinfected with HIV-HCV. This is a real-world retrospective single-center study of patients followed in the HIV clinic between 2002 and 2018. Linkage to care was defined as achieving care cascade steps: (1) hepatology clinic visit, (2) receiving prescription of anti-HCV treatment, and (3) documentation of sustained virologic response (SVR). Of 1660 patients with HIV, 254 with HIV-HCV coinfection were included. Only 39% of them achieved SVR. The rate limiting step was the engagement into hepatology care. Being a PWID was associated with ~50% reduced odds of achieving study outcomes, active drug use was associated with ~90% reduced odds. Older age was found to facilitate treatment success. Once treated, the rate of SVR was high in all populations. HCV is undertreated in coinfected young PWIDs. Further efforts should be directed to improve access to care in this marginalized population.

Humoral Response to the Third Dose of Sars-Cov-2 Vaccine in Kidney Transplant Recipients.

BACKGROUND: Most solid organ transplant recipients did not develop an appreciable serologic response after 2 doses of the mRNA SARS-CoV-2 vaccine. METHODS: We analyzed the humoral response after a third dose of the BNT162b2 vaccine in 130 kidney transplant recipients, compared to 48 health care workers, and associated factors, including prevaccine cellular immune response, by evaluating intracellular cytokine production after stimulation of donor's peripheral blood mononuclear cells. RESULTS: After 2 doses, most of the controls (47 out of 48, 98%) and only 40% of kidney recipients (52 of 130) kidney recipients were seropositive (P < .001). Most seronegative recipients developed a serologic response after the booster (47 out 78, 60%), thus bringing the total number of seropositive recipients to 99 out of 130 (76%). After the third dose, there was a significant increase in antibodies titers in both groups. Decreased humoral response was significantly associated with an older age, lower lymphocyte count, and a lower level of antibodies before booster administration. CD4+TNFα+ and CD4+INFγ+ were correlated with mean increase in antibody titers. CONCLUSIONS: A third dose of the BNT162b2 mRNA vaccine in kidney recipients is safe and effectively results in increased IgG anti-S levels, including in individuals who were seronegative after 2 doses. Long-term studies of the length of the immune response and protection are required.

The effect of a third-dose BNT162b2 vaccine on anti-SARS-CoV-2 antibody levels in immunosuppressed patients.

OBJECTIVES: The recent surge in coronavirus disease 2019 cases led to the consideration of a booster vaccine in previously vaccinated immunosuppressed individuals. However, the immunogenic effect of a third-dose severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine in immunosuppressed patients is still unknown. METHODS: This was an observational cohort study of 279 previously vaccinated immunosuppressed patients followed at a single tertiary hospital in Israel. Patients were administered a third dose of the Pfizer-BioNTech mRNA vaccine (BNT162b2) between July 14 and July 21, 2021. Levels of IgG antibodies against the spike receptor-binding domain of SARS-CoV-2 were measured 3 to 4 weeks after vaccination. RESULTS: Of the cohort of 279 patients, 124 (44.4%) had haematologic malignancies, 57 (20.4%) had rheumatologic diseases, and 98 (35.1%) were solid organ-transplant recipients. Anti-SARS-CoV-2 antibody levels increased in 74.9% of cases. Across the entire cohort, the median absolute antibody levels (expressed in AU/mL) increased from 7 (interquartile range (IQR), 0.1-69) to 243 (IQR, 2-4749) after the booster dose. The response significantly varied across subgroups: The transplant cohort showed the greatest increase in absolute antibody levels (from 52 (IQR, 7.25-184.5) to 1824 (IQR, 161-9686)), followed by the rheumatology (from 22 (IQR, 1-106) to 1291 (IQR, 6-6231)) and haemato-oncology (from 1 (IQR, 0.1-7) to 7.5 (IQR, 0.1-407.5)) cohorts. The χ2 test was 8.30 for difference in fold change (p = 0.016). Of the 193 patients who were seronegative at baseline, 76 became seropositive after vaccination, corresponding to a 39.4% (95% CI, 32.8%-46.4%) seroconversion rate. Transplant patients had the highest seroconversion rate (58.3% (95% CI, 44.3%-71.2%)), followed by rheumatology (44.1% (95% CI, 28.9%-60.5%)) and haemato-oncology (29.7% (95% CI, 22%-38.8%); χ2 = 11.87; p = 0.003) patients. DISCUSSION: A third dose of BNT162b2 is immunogenic in most immunosuppressed individuals, although antibody response may differ based on the type of disease and immunosuppression. The antibody level that correlates with protection is still unknown; thus, future studies are needed to evaluate clinical outcomes.

Prevalence of Bleeding and Thrombosis in Critically Ill Patients with Chronic Liver Disease.

INTRODUCTION: Hemorrhage and venous thromboembolism (VTE) are recognized complications of chronic liver disease (CLD), but their prevalence and risk factors in critically ill patients are uncertain. PATIENTS AND METHODS: We studied a retrospective cohort of patients with CLD nonelectively admitted to a specialist intensive care unit (ICU) determining the prevalence and timing of major bleeding and VTE (early, present on admission/diagnosed within 48 hours; later, diagnosed >48 hours post-ICU admission). Associations with baseline clinical and laboratory characteristics, multiorgan failure (MOF), blood product administration, and mortality were explored. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression. RESULTS: Of 623 patients with median age 52, bleeding (>48 hours after admission) occurred in 87 (14%) patients. Bleeding was associated with greater illness severity and increased mortality. Gastrointestinal bleeding accounted for 72% of events, secondary to portal hypertension in >90%. Procedure-related bleeding was uncommon. VTE occurred in 125 (20%) patients: early VTE in 80 (13%) and involving the portal vein in 85%. Later VTE affected 45 (7.2%) patients. Hepatocellular carcinoma (HCC) and nonalcoholic liver disease were independently associated with early VTE (OR: 2.79, 95% CI: 1.5-5.2 and OR: 2.32, 95% CI: 1.4-3.9, respectively), and HCC, sepsis, and cryoprecipitate use with late VTE (OR: 2.45, 95% CI: 1.11-5.43; OR: 2.26, 95% CI: 1.2-4.3; and OR: 2.60, 95% CI: 1.3-5.1). CONCLUSION: VTE was prevalent on admission to critical care and less commonly developed later. Bleeding was associated with MOF and increased mortality. Severe MOF was not associated with an increased rate of VTE which was linked with HCC, and specific etiologies of CLD.

Chronic schistosomiasis in African immigrants in Israel: Lessons for the non-endemic setting.

To study the clinical presentation of Chronic Schistosomiasis (CS) in immigrants from East Africa to Israel and the tests that were useful in confirming the diagnosis.A retrospective study of all medical notes pertaining to hospitalized patients who were immigrants from East Africa with a pathological or microscopic confirmation of CS. Literature review was also conducted focusing on diagnosis of schistosomiasis among immigrants from endemic countries.We identified 32 suspected and 11 confirmed cases of CS. Most of the patients (82%) presented with gastrointestinal symptoms. Sensitivity of stool smear, serology and tissue diagnosis (by histopathology or microscopy) were 14%, 100%, 89%, respectively. Patients have undergone extensive diagnostic evaluation with long hospitalization stays (median 10 days, range 4 to 33 days).CS has multiple presentations and is seen in Israel among refugees from Eritrea and Sudan. Most of the manifestations are gastrointestinal, suggestive of infection with Schistosoma mansoni (S. mansoni). Standard diagnostic techniques used in endemic countries, such as microscopy for ova and parasites were unhelpful, necessitating more advanced procedures like colonoscopic or liver biopsy. We propose a diagnostic algorithm for CS in this patient population in order to make an accurate diagnosis and avoid unnecessary invasive procedures.

Withholding Treatment From the Dying Patient: The Influence of Medical School on Students' Attitudes.

PURPOSE: To determine motives and attitudes towards life-sustaining treatments (LSTs) by clinical and preclinical medical students. METHODS: This was a scenario-based questionnaire that presented patients with a limited life expectancy. The survey was distributed among 455 medical students in preclinical and clinical years. Students were asked to rate their willingness to perform LSTs and rank the motives for doing so. The effect of medical education was then investigated after adjustment for age, gender, religion, religiosity, country of origin, and marital status. RESULTS: Preclinical students had a significantly higher willingness to perform LSTs in all cases. This was observed in all treatments offered in cases of a metastatic oncologic patient and an otherwise healthy man after a traumatic brain injury (TBI). In the case of an elderly woman on long-term care, preclinical students had higher willingness to supply vasopressors but not perform an intubation, feed with a nasogastric tube, or treat with a continuous positive air-pressure ventilator. Both preclinical and clinical students had high willingness to perform resuscitation on a twelve-year-old boy with a TBI. Differences in motivation factors were also seen. DISCUSSION: Preclinical students had a greater willingness to treat compared to clinical students in all cases and with most medical treatments offered. This is attributed mainly to changes along the medical curriculum. Changes in reasons for supplying LSTs were also documented.

Clinical management of acute liver failure: Results of an international multi-center survey.

AIM: To assess the practice of caring for acute liver failure (ALF) patients in varying geographic locations and medical centers. METHODS: Members of the European Acute Liver Failure Consortium completed an 88-item questionnaire detailing management of ALF. Responses from 22 transplantation centers in 11 countries were analyzed, treating between 300 and 500 ALF cases and performing over 100 liver transplants (LT) for ALF annually. The questions pertained to details of the institution and their clinical activity, standards of care, referral and admission, ward- based care versus intensive care unit (ICU) as well as questions regarding liver transplantation - including criteria, limitations, and perceived performance. Clinical data was also collected from 13 centres over a 3 mo period. RESULTS: The interval between referral and admission of ALF patients to specialized units was usually less than 24 h and once admitted, treatment was provided by a multidisciplinary team. Principles of care of patients with ALF were similar among centers, particularly in relation to recognition of severity and care of the more critically ill. Centers exhibited similarities in thresholds for ICU admission and management of severe hepatic encephalopathy. Over 80% of centers administered n-acetyl-cysteine to ICU patients for non-paracetamol-related ALF. There was significant divergence in the use of prophylactic antibiotics and anti-fungals, lactulose, nutritional support and imaging investigations in admitted patients and in the monitoring and treatment of intra-cranial pressure (ICP). ICP monitoring was employed in 12 centers, with the most common indications being papilledema and renal failure. Most patients listed for transplantation underwent surgery within an average waiting time of 1-2 d. Over a period of 3 mo clinical data from 85 ALF patients was collected. Overall patient survival at 90-d was 76%. Thirty six percent of patients underwent emergency LT, with a 90% post transplant survival to hospital discharge, 42% survived with medical management alone. CONCLUSION: Alongside similarities in principles of care of ALF patients, major areas of divergence were present in key areas of diagnosis, monitoring, treatment and decision to transplant.

Dipeptidyl peptidase 4-deficient rats have improved bile secretory function in high fat diet-induced steatosis.

BACKGROUND/AIMS: Rodent obesity models have been shown to display impaired bile secretory functions. We have shown that glucagon-like peptide 1 (GLP-1) attenuates hepatic lipogenesis, and in the present study we investigated whether GLP-1 also improves high fat diet-associated cholestatic injury. METHODS: Wild type (WT) and dipeptidyl peptidase 4-deficient rats (DPP4-) with chronic elevated serum levels of active GLP-1 were fed regular chow and a Western diet for 2 months. Primary hepatocytes were used to assess GLP-1 effects on mRNA expression and transcription of genes encoding bile acid synthesis enzymes and transporters. RESULTS: DPP4- exhibited attenuated liver injury as expressed by lower serum AST and ALT after 2 months of a Western diet. In addition, DPP4- had better insulin sensitivity, lower serum triglycerides, cholesterol and bile acids. Hepatic expression of cyp7A1, the rate limiting enzyme in conversion of cholesterol into bile acids, was strongly attenuated in DPP4- fed with a Western diet. Moreover, hepatic expression of bile transporter, ABCB11, was increased, facilitating a higher rate of bile secretion. Mechanistically, we showed that GLP-1 directly reduced basal and LXR-induced cyp7A1 mRNA expression and suppressed cyp7A1 transcription in transient transfection assays in primary hepatocytes. However, GLP-1 and its analog exendin 4 also induced mRNA expression of bile acid transporter ABCC3 in primary rat hepatocyte cultures. CONCLUSIONS: Our data suggest that GLP-1 analogs may serve as a novel therapeutic drug to alleviate obesity-induced liver injury by reducing bile acid synthesis and improving liver bile secretory function.

Mycophenolic acid suppresses human pterygium and normal tenon fibroblast proliferation in vitro.

AIMS: To investigate whether mycophenolic acid (MPA) exerts antifibrotic effects on pterygium fibroblasts (PFB) with and without stimulation with fibrogenic cytokines, and to compare the efficacy of MPA with mitomycin (MMC) and dexamethasone (DXM) on PFB and tenon fibroblasts (TFB). METHODS: TFB and PFB were obtained from tissue explants during strabismus or pterygium surgery. Proliferation of subconfluent fibroblasts ± basic fibroblast growth factor (bFGF) (10 ng/ml) was assessed by using the (3H) thymidine-incorporation assay. Cell cultures were incubated with MPA, MMC or DXM. Apoptosis was evaluated by quantifying Annexin V and propidium iodide positive cells with flow cytometry. RESULTS: MPA showed a concentration-dependent inhibition of proliferation of PFB ± bFGF as well as TFB ± bFGF. The antiproliferative effect of MPA was comparable with that of MMC and DXM. Short exposure of PFB to MPA under profibrogenic conditions was significantly inhibitory. No apoptotic effect was found on TFB. CONCLUSIONS: MPA suppressed tenon and pterygium fibroblast proliferation in vitro under basal and profibrogenic conditions. It was comparable with MMC under long-term exposure, but MMC was more suppressive under short-term exposure. MPA may be safer than MMC due to a more specific mechanism of action and lack of cytotoxicity. Further investigation is warranted regarding MPA concentrations that will lead to a potent antiproliferative effect in vivo.