Hepatic safety and efficacy of immunomodulatory drugs used in patients with autoimmune hepatitis.

BACKGROUND AND AIMS: There is little data on the hepatic efficacy and safety of immunomodulatory drugs used in patients with autoimmune hepatitis (AIH), despite their established use in dermatology, rheumatology and inflammatory bowel diseases (IBD). Our aim was to collect real-life data on the experience of expert centres in treating AIH patients with these drugs, considered unconventional for AIH management. METHODS: Online survey among hepatology centres being part of the European Reference Network on Hepatological Diseases (ERN RARE-LIVER). RESULTS: 25 AIH patients have been reported. Ten were female, median age at diagnosis was 28 years; median follow-up was 17 months. All had initially received AIH-standard treatment. AIH-unconventional treatment was initiated for concomitant autoimmune diseases in 15 cases: nine for IBD (five vedolizumab and four ustekinumab), and one each for following diseases: autoinflammatory syndrome (tocilizumab), chronic urticaria (omalizumab), rheumatoid arthritis (abatacept), psoriasis (guselkumab), psoriatric arthritis (secukinumab, followed by ustekinumab) and alopecia (ruxolitinib). Three patients were treated with immunomodulatory drugs for side effects of previous treatments, including two patients with IBD treated with vedolizumab and ustekinumab, respectively, and one treated with belimumab. At the end of follow-up, 13 patients were in complete biochemical response, the patient on omalizumab had a relapse, and four patients with concomitant IBD had insufficient response. Seven patients were treated for lack of biochemical remission, of whom six with belimumab, all initially reaching complete biochemical response, but five relapsing during follow-up; and one with secukinumab, having concomitant rheumatoid arthritis and ankylosing spondylitis, reaching complete biochemical response. Only the patient on abatacept received unconventional treatment as monotherapy. Side effects were reported in two patients on belimumab: one recurrent soft tissue infections, one fatigue and arthralgia. CONCLUSION: Among 25 AIH patients who were treated with immunomodulatory drugs for different reasons, the majority had a fovorable course, relapse was frequent in difficult-to-treat patients who received belimumab, and four with concomitant IBD had insufficient response.

Quantification of polyreactive immunoglobulin G facilitates the diagnosis of autoimmune hepatitis.

BACKGROUND AND AIMS: Detection of autoantibodies is a mainstay of diagnosing autoimmune hepatitis (AIH). However, conventional autoantibodies for the workup of AIH lack either sensitivity or specificity, leading to substantial diagnostic uncertainty. We aimed to identify more accurate serological markers of AIH with a protein macroarray. APPROACH AND RESULTS: During the search for more-precise autoantibodies to distinguish AIH from non-AIH liver diseases (non-AIH-LD), IgG antibodies with binding capacities to many human and foreign proteins were identified with a protein macroarray and confirmed with solid-phase ELISAs in AIH patients. Subsequently, polyreactive IgG (pIgG) was exemplarily quantified by reactivity against human huntingtin-interacting protein 1-related protein in bovine serum albumin blocked ELISA (HIP1R/BSA). The diagnostic fidelity of HIP1R/BSA binding pIgG to diagnose AIH was assessed in a retrospective training, a retrospective multicenter validation, and a prospective validation cohort in cryoconserved samples from 1,568 adults from 10 centers from eight countries. Reactivity against HIP1R/BSA had a 25% and 14% higher specificity to diagnose AIH than conventional antinuclear and antismooth muscle antibodies, a significantly higher sensitivity than liver kidney microsomal antibodies and antisoluble liver antigen/liver pancreas antigen, and a 12%-20% higher accuracy than conventional autoantibodies. Importantly, HIP1R/BSA reactivity was present in up to 88% of patients with seronegative AIH and in up to 71% of AIH patients with normal IgG levels. Under therapy, pIgG returns to background levels of non-AIH-LD. CONCLUSIONS: pIgG could be used as a promising marker to improve the diagnostic workup of liver diseases with a higher specificity for AIH compared to conventional autoantibodies and a utility in autoantibody-negative AIH. Likewise, pIgG could be a major source of assay interference in untreated AIH.

Confidence in treatment is contributing to quality of life in autoimmune liver diseases. The results of ERN RARE-LIVER online survey.

BACKGROUND AND AIMS: Autoimmune liver diseases (AILDs) are associated with impaired health-related quality of life (HrQoL). The aim of this project was to identify potentially modifiable factors related to HrQoL in a large transnational cohort of patients with AILDs. METHODS: A cross-sectional online survey was conducted on patients with autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) or primary sclerosing cholangitis from 15 European countries. HrQoL was measured with EQ-5D-5L and EQ visual analogue scale (EQ-VAS) and analysed in relation to demographic, psychosocial, disease- and treatment-related factors. A Patient Health Questionnaire-2 score >3 indicated relevant depression. Multivariable linear regression analyses were used to identify potentially modifiable factors associated with HrQoL and confidence in treatment whilst adjusting for known confounders. RESULTS: A group of 1178 European patients (79% female, mean age 48 ± 14 years) participated in the study. HrQoL was impaired in all three diseases (mean EQ-5D-5L = 0.75, mean EQ VAS = 68.9), most markedly in PBC (mean EQ-5D-5L = 0.73, mean EQ-VAS = 66.2). Relevant depression, which was detected in 17% of patients, was prominently associated with impaired HrQoL. In the regression analysis, treatment confidence was identified as an important modifiable factor positively contributing to HrQoL. This influence was observable even after adjusting for other covariates including depression. Management in a transplant centre, treatment with azathioprine in AIH, and with ursodeoxycholic acid in PBC, was associated with increased treatment confidence. Finally, improved patient-physician relationships contributed to treatment confidence. CONCLUSION: Treatment confidence is a relevant modifiable determinant of HrQoL and should be further investigated to improve the standards of care for patients with AILDs.

Improving quality of life in patients with rare autoimmune liver diseases by structured peer-delivered support (Q.RARE.LI): study protocol for a transnational effectiveness-implementation hybrid trial.

BACKGROUND: Psychosocial support is a crucial component of adequate rare disease care, but to date psychosocial support needs of this patient population are insufficiently met. Within Q.RARE.LI, we strive to evaluate the effectiveness of a structured, transdiagnostic, and location-independent psychosocial support intervention in routine care of patients with rare autoimmune liver diseases in five countries and prepare its implementation. METHODS: Within an effectiveness-implementation hybrid trial, we aim to a) investigate the effectiveness of the intervention in routine care in five diverse healthcare systems and b) assess implementation outcomes, examine and prepare the implementation context, and develop country-specific implementation strategies. To assess effectiveness, we will include N = 240 patients with rare autoimmune liver diseases. Within a two-armed randomized controlled trial (allocation ratio 1:1), we will compare structured and peer-delivered psychosocial support in addition to care-as-usual (CAU) with CAU alone. Outcomes will be assessed via electronic database entry prior to intervention, directly after, and at a three-month follow-up. Our primary effectiveness outcome will be mental health-related quality of life at post-assessment. Secondary outcomes include depression and anxiety severity, perceived social support, helplessness, and disease acceptance. Implementation outcomes will be assessed within a mixed-methods process evaluation. In a quantitative cross-sectional survey, we will examine perceived acceptability and feasibility in patients, peer-counselors, and healthcare providers involved in delivery of the intervention. In qualitative focus groups, we will analyze the implementation context and determine barriers and facilitators for implementation with different stakeholders (patients and/or representatives, peer-counselors, healthcare providers, health insurers). Based on these results, we will derive country-specific implementation strategies and develop a concrete implementation plan for each country. DISCUSSION: The intervention is expected to help patients adjust to their disease and improve their mental quality of life. The transdiagnostic and location-independent program has the potential to reach patients for psychosocial support who are usually hard to reach. By preparing the implementation in five countries, the project can help to make low-threshold psychosocial support available to many patients with rare diseases and improve comprehensive healthcare for an often neglected group. TRIAL REGISTRATION: ISRCTN15030282.

Risk factors and outcomes associated with recurrent autoimmune hepatitis following liver transplantation.

BACKGROUND & AIMS: Autoimmune hepatitis can recur after liver transplantation (LT), though the impact of recurrence on patient and graft survival has not been well characterized. We evaluated a large, international, multicenter cohort to identify the probability and risk factors associated with recurrent AIH and the association between recurrent disease and patient and graft survival. METHODS: We included 736 patients (77% female, mean age 42±1 years) with AIH who underwent LT from January 1987 through June 2020, among 33 centers in North America, South America, Europe and Asia. Clinical data before and after LT, biochemical data within the first 12 months after LT, and immunosuppression after LT were analyzed to identify patients at higher risk of AIH recurrence based on histological diagnosis. RESULTS: AIH recurred in 20% of patients after 5 years and 31% after 10 years. Age at LT ≤42 years (hazard ratio [HR] 3.15; 95% CI 1.22-8.16; p = 0.02), use of mycophenolate mofetil post-LT (HR 3.06; 95% CI 1.39-6.73; p = 0.005), donor and recipient sex mismatch (HR 2.57; 95% CI 1.39-4.76; p = 0.003) and high IgG pre-LT (HR 1.04; 95% CI 1.01-1.06; p = 0.004) were associated with higher risk of AIH recurrence after adjusting for other confounders. In multivariate Cox regression, recurrent AIH (as a time-dependent covariate) was significantly associated with graft loss (HR 10.79, 95% CI 5.37-21.66, p <0.001) and death (HR 2.53, 95% CI 1.48-4.33, p = 0.001). CONCLUSION: Recurrence of AIH following transplant is frequent and is associated with younger age at LT, use of mycophenolate mofetil post-LT, sex mismatch and high IgG pre-LT. We demonstrate an association between disease recurrence and impaired graft and overall survival in patients with AIH, highlighting the importance of ongoing efforts to better characterize, prevent and treat recurrent AIH. LAY SUMMARY: Recurrent autoimmune hepatitis following liver transplant is frequent and is associated with some recipient features and the type of immunosuppressive medications use. Recurrent autoimmune hepatitis negatively affects outcomes after liver transplantation. Thus, improved measures are required to prevent and treat this condition.

Measurement of liver and spleen stiffness as complementary methods for assessment of liver fibrosis in autoimmune hepatitis.

BACKGROUND AND AIMS: Liver stiffness measurements (LSM), commonly performed by transient elastography (TE) or two-dimensional shear wave elastography (2D-SWE), are used to quantify liver fibrosis. Active hepatitis, a hallmark of autoimmune hepatitis (AIH), could bias LSM. This bias might be overcome by measurement spleen 2D-SWE. Here, we compare liver and spleen 2D-SWE to TE and liver biopsy (LB) in prospectively recruited patients with AIH. METHODS: We analysed liver and spleen 2D-SWE in relation to liver TE in 90 patients treated ≥ 6 months for AIH. Liver and spleen 2D-SWE were also compared to LB in 63 individuals with AIH. Finally, we evaluated these tools in 220 patients with AIH and during 18 months follow-up. RESULTS: Liver 2D-SWE correlated with surrogate markers of active hepatitis (ALT and IgG, both P < .001) but there was no link between spleen 2D-SWE and ALT. Liver 2D-SWE, but not spleen 2D-SWE, was associated with histopathological inflammatory score (P < .01). When compared to LB, the optimal cut-offs for detecting cirrhosis by liver and spleen 2D-SWE were 16.1 kPa (AUROC 0.93) and 29.8 kPa (AUROC 0.95), respectively. In patients with active hepatitis the combined diagnostic approach including liver and spleen 2D-SWE had significantly better AUROC for detecting cirrhosis than liver 2D-SWE alone. CONCLUSIONS: Liver and spleen 2D-SWE are reliable complementary methods for the diagnosis of advanced fibrosis in AIH. Spleen 2D-SWE seems to be less biased by inflammation and could facilitate fibrosis assessment in therapy-naïve patients or in the presence of active hepatitis.

COVID-19: Focus on the lungs but do not forget the gastrointestinal tract.

The coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 was declared in the last weeks as global pandemic. Currently affecting more than 5 000 000 individuals worldwide, COVID-19 is most commonly associated with symptoms caused by the acute respiratory distress syndrome (ARDS). As the number of infected individuals increases, we are learning that not only lungs, but also other organs can be affected by the virus. The gastrointestinal symptoms, for example diarrhoea, vomiting, nausea or abdominal pain, are frequent in patients with COVID-19. Moreover, alimentary tract symptoms may precede the respiratory presentation of SARS-CoV-2 infection. This can lead to delayed diagnosis and inappropriate management of infected patients. In addition, SARS-CoV-2 nucleic acid can be detected in faeces of infected patients and rectal swabs are even reported to remain positive for a longer period of time than nasopharyngeal swabs. Here, we aim to provide an update on the gastrointestinal involvement of COVID-19 presenting the symptoms that can be encountered in infected patients. We address the role of angiotensin-converting enzyme 2 (ACE2), as a functional receptor for SARS-CoV-2, which also was found in the gastrointestinal tract. Finally, we briefly discuss faecal shedding of SARS-CoV-2 and its potential role in the pathogenesis of the disease.

Acute-On-Chronic Liver Failure: The Role of Prognostic Scores in a Single-Center Experience.

BACKGROUND Acute-on-chronic liver failure (ACLF) is associated with multi-organ failure and high short-term mortality. We evaluated the role of currently available prognostic scores for prediction of 90-day mortality in ACLF patients. MATERIAL AND METHODS Fifty-five (M/F=40/15, mean age 60.0±11.1years) consecutive cirrhotic patients with severe liver insufficiency (mean MELD 28.4±9.0, Child-Pugh score - C-12) were enrolled into the study. MELD variants and SOFA, CLIF-SOFA, and CLIF-C scores were calculated, mortality predicting factors were identified, and clinical comparisons between ACLF and AD patients were performed. RESULTS In total, 30 (55%) patients were transplanted (22 ACLF and 8 AD), and 20 (30%) died (19 ACLF and 1 AD). Five (9%) patients survived without liver transplantation (LT) (3 ACLF and 2 AD), and 3 transplant recipients died within 1 month. SOFA, CLIF-SOFA, CLIF-C OF, and INR were significantly associated with the incidence of 90-day mortality in competing risk regression analysis (all p<0.001). The model based on SOFA had the lowest BIC, with the optimal cut-off for 90-day mortality prediction ≥12, with the area under the receiver operating characteristic (AUROC) of 0.901 (95% CI 0.779-1.000; p<0.001), and corresponding incidence of transplantation rates of 85.5% and 11.8%, respectively (p<0.001). Of note, the important role of 24-h urine output is emphasized. CONCLUSIONS In this series of ACLF patients, SOFA score outperformed the CLIF-C scores in predicting 90-day mortality. Multi-organ failure scores performed better in predicting patient mortality than conventional liver function assessment. LT is possible and remains effective in selected ACLF patients.

Autoimmune hepatitis exerts a profound, negative effect on health-related quality of life: A prospective, single-centre study.

BACKGROUND AND AIMS: Autoimmune hepatitis is a progressive chronic liver disease. Health-related quality of life in autoimmune hepatitis has not attracted much attention so far. We prospectively assessed various aspects of health-related quality of life in a well characterized group of patients with autoimmune hepatitis. METHODS: In total, 140 patients with autoimmune hepatitis (mean age 40 ± 17 years) and 170 controls (mean age 36 ± 14 years) were included. Health-related quality of life was evaluated with following questionnaires: The Short Form (36) Health Survey, Modified Fatigue Impact Score, State-Trait Anxiety Inventory and Patient Health Questionnaire-9 assessing depression. RESULTS: Patients with autoimmune hepatitis showed a significant impairment of health-related quality of life in all, but one, domains of The Short Form (36) Health Survey. Autoimmune hepatitis was associated with pronounced physical fatigue (P < 0.001), anxiety (P < 0.001) and depression (P < 0.001). As compared to males, female patients demonstrated greater impairment of physical aspects of The Short Form (36) Health Survey and Modified Fatigue Impact Score. Twenty-seven patients (19%) had moderate (Patient Health Questionnaire-9 >10) and 14 (10%) moderately severe depression (Patient Health Questionnaire-9 >15). Depression showed a very strong correlation with chronic fatigue (R = 0.68; P < 0.001); physical and mental components of The Short Form (36) Health Survey (R = 0.52/0.68 respectively; P < 0.001) and anxiety (R = 0.47; P < 0.001). There was a trend towards better life's quality in patients treated with budesonide in some aspects of their health-related quality of life. Duration of the disease, age at diagnosis, liver fibrosis and the presence of cirrhosis were not associated with health-related quality of life. CONCLUSIONS: Health-related quality of life is significantly impaired in patients with autoimmune hepatitis. Depression seems to be a dominant symptom affecting their well-being, not associated with clinical and biochemical features of the disease.

Air pollution may affect the assessment of smoking habits by exhaled carbon monoxide measurements.

BACKGROUND: While European air quality policies reduce ambient carbon monoxide (CO) concentrations in general, there are still areas affected by high environmental CO exposure from transportation, industry and burning low-quality fossil fuels. We investigated, how these CO amounts might influence exhaled CO measurements used to monitor the smoking status of healthy subjects. METHODS: A cross-sectional study of healthy adults living in areas of high air pollution (N = 742) and low air pollution (N = 197) in Poland. They completed a survey regarding their smoking habits and underwent necessary body measurements including exhaled CO concentration levels. RESULTS: Ambient CO levels were much higher in highly pollutes cities. Also exhaled CO levels in subjects from high pollution areas were significantly higher, independent of subject smoking status (8.25 ppm vs. 3.26 ppm). Smokers exhaled more CO than non-smokers. Although the duration of smoking did not affect the CO levels, they were proportional to the number of cigarettes smoked during the day, especially for higher amounts of cigarettes and in unpolluted areas. It was possible to differentiate active from passive smokers in all areas, but the difference for passive smokers vs. non-smokers was significant only in low pollution city inhabitants. CONCLUSIONS: Exhaled CO levels were confirmed to be a good indicator of smoking status and smoking pattern in healthy subjects. However, high environmental CO levels both increase baseline exhaled CO concentrations in non-smokers affecting their discrimination from passive smokers, and obscure categorizing cigarette consumption in heavy smokers. These findings add important evidence on both understanding of exhaled CO monitoring results and a significance of environmental CO exposure in areas with high pollution.

Influence of air pollution on exhaled carbon monoxide levels in smokers and non-smokers. A prospective cross-sectional study.

BACKGROUND: The poor air quality and cigarette smoking are the most important reasons for increased carbon monoxide (CO) level in exhaled air. However, the influence of high air pollution concentration in big cities on the exhaled CO level has not been well studied yet. OBJECTIVES: To evaluate the impact of smoking habit and air pollution in the place of living on the level of CO in exhaled air. METHODS: Citizens from two large cities and one small town in Poland were asked to complete a survey disclosing their place of residence, education level, work status and smoking habits. Subsequently, the CO level in their exhaled air was measured. Air quality data, obtained from the Regional Inspectorates of Environmental Protection, revealed the differences in atmospheric CO concentration between locations. RESULTS: 1226 subjects were divided into 4 groups based on their declared smoking status and place of living. The average CO level in exhaled air was significantly higher in smokers than in non-smokers (p<0.0001) as well as in non-smokers from big cities than non-smokers from small ones (p<0.0001). Created model showed that non-smokers from big cities have odds ratio of 125.3 for exceeding CO cutoff level of 4ppm compared to non-smokers from small towns. CONCLUSIONS: The average CO level in exhaled air is significantly higher in smokers than non-smokers. Among non-smokers, the average exhaled CO level is significantly higher in big city than small town citizens. These results suggest that permanent exposure to an increased concentration of air pollution and cigarette smoking affect the level of exhaled CO.

Gamma Knife Radiosurgery for Pediatric Arteriovenous Malformations: A Canadian Experience.

BACKGROUND: Gamma Knife (GK) radiosurgery for pediatric arteriovenous malformations (AVM) of the brain presents a non-invasive treatment option. We report our institutional experience with GK for pediatric AVMs. METHODS: We performed a retrospective review of all pediatric patients treated with GK for cerebral AVMs at our institution from November 2003 up to and including September 2014. Patient demographics, AVM characteristics, treatment parameters and AVM responses were recorded. RESULTS: Nineteen patients were treated, with 4 lost to follow-up. The mean age was 14.2 years (range. 7-18 years), with 10 being males (52.6%). The mean AVM diameter and volume were 2.68 cm and 3.10 cm3 respectively. The mean Spetzler-Martin (SM) and Pollock grades of the treated AVMs were 2.4 and 0.99 respectively. The mean follow-up was 62 months. All AVMs treated demonstrated a response on follow-up imaging. Nine of 15 (60.0%) patients displayed obliteration of their AVMs. Nine of 11 patients with a minimum of 3 years follow-up (81.8%) displayed obliteration, with SM and Pollock grades correlating to the chance of obliteration in this group. Two patients developed post-GK edema requiring short course dexamethasone therapy. No other major complications occurred. No permanent complications occurred. CONCLUSIONS: GK radiosurgery for pediatric AVMs offers a safe and effective treatment option, with low permanent complication rates during early follow-up.

Previous hepatitis E virus infection is associated with increased liver stiffness in patients with autoimmune hepatitis.

INTRODUCTION: Autoimmune hepatitis (AIH) is a chronic, progressive liver disease that, in most cases, may require lifelong immunosuppression. Hepatitis E virus (HEV) is a leading cause of acute, typically self­limited hepatitis worldwide, although immunocompromised patients may develop chronic hepatitis. OBJECTIVES: We aimed to evaluate the impact of HEV seropositivity on the clinical course of AIH. PATIENTS AND METHODS: The study involved a group of 374 adult patients with AIH (68% women; median [interquartile range] age, 34 [18-83] years; 38% with liver cirrhosis). Serum HEV immunoglobulin (Ig) G and IgM antibodies were measured by enzyme­linked immunosorbent assay, liver fibrosis was assessed by liver stiffness measurement (LSM), and liver cirrhosis was confirmed with liver histology or LSM. RESULTS: Fifty­five patients (15%) with AIH were HEV IgG­positive. These patients were older (P <0.001), had higher body mass index, and higher value of LSM (both P <0.05). In a multivariable model including the levels of alanine aminotransferase and IgG, the HEV seropositive status was associated with an increased risk of advanced liver fibrosis with odds ratio of 3.69 (95% CI, 1.26-10.77; P = 0.02), as reflected by liver stiffness equal to or above 10.5 kPa. HEV IgG seropositivity was, however, not linked with the type of treatment or worse AIH outcome. Seroprevalence of HEV in the patients with AIH was lower than in the general population of Polish blood donors (43%). CONCLUSIONS: Patients with AIH and HEV IgG­positive status seem to be at risk of more advanced liver fibrosis. However, the overall seroprevalence of HEV IgG is lower in patients with AIH than in blood donors in Poland.

Variants of autoimmune liver diseases: how to diagnose and treat them?

Autoimmune liver diseases (AILDs), such as autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC), and primary biliary cholangitis (PBC), are classified as rare diseases, but their incidence is increasing. In this review, we present the characteristics of AILDs in adults, and mainly focus on their variants in terms of diagnosis and management. The classic AILDs have been well defined in clinical guidelines, but a proportion of patients with a single AILD tend to show features of other AILDs. In these cases, AIH­PSC or AIH­PBC variants should be suspected, prompting evaluation in experienced centers. These variants are more representative of clinical categories rather than pathological diagnoses, and the leading component of the disease determines its treatment. However, treating these patients is challenging, even for experienced clinicians. Progression to end­stage liver disease is, unfortunately, not a rare course, despite combined and second­line therapies, particularly for AIH­PSC variants. Thus, studies based on prospective registers are necessary to elaborate upon widely accepted guidelines, to offer better care to these patients, and to improve their prognosis.

Health-related quality of life and symptoms in autoimmune liver diseases.

Assessment of Health-Related Quality of Life (HRQoL) has emerged as an important tool in the evaluation of both the well-being of patients and the results of their clinical management. Over the years, a large number of questionnaires focusing on various aspects of quality of life have been developed. They are frequently divided into generic questionnaires, which can be used under various conditions, disease-specific and symptom-specific questionnaires. Autoimmune liver diseases, such as autoimmune hepatitis, primary sclerosing cholangitis, or primary biliary cirrhosis, comprise a group of rare liver conditions (i.e. affecting fewer than 5 in 10,000 people in the general population). Unfortunately, HRQoL has not been well-studied in this group of patients. In this review, we comprehensively summarize the data available in the literature on HRQoL in these conditions, emphasizing the important role that quality of life plays in the successful management of such patients.

SARS­CoV­2 vaccination in liver transplant recipients: factors affecting immune response and refusal to vaccine.

INTRODUCTION: The effectiveness of SARS­CoV­2 vaccination in liver transplant (LT) recipients varies between reports. OBJECTIVES: In this study, we analyzed the immune response to the SARS­CoV­2 vaccine, factors affecting the response, and reasons for the vaccine refusal. PATIENTS AND METHODS: Among 300 consecutive LT recipients, 75% were vaccinated. The humoralresponse was assessed by the quantitative determination of antitrimeric spike protein­specific IgG antibodies to SARS­CoV­2. Thirty­four vaccinated patients with prior SARS­CoV­2 infection were analyzed separately. RESULTS: Among 192 LT recipients vaccinated without past natural infection, 69% developed the immune response (median time of 125 days after the second dose). Older age, worse kidney function, and dual immunosuppression negatively affected the humoral response. Mycophenolate mofetil increased the risk of nonresponse (odds ratio [OR], 2.99; 95% CI, 1.45-6.19). The antibody concentration was higher in the first 90 days from the second dose and stable as compared with 90-150 days and over 150 days. LT recipients with prior COVID­19 presented with a robust immune response (100%). The female sex, living in a rural area, lower body mass index, and younger age (all P <0.05) were associated with the refusal of the vaccine. CONCLUSIONS: The lower immune response in the vaccinated LT recipients than in the general population justifies administering the third dose of the vaccine. However, more data are needed to recommend any therapy modification before the vaccination.

Clinical Implication of Plasma CD163 in Patients With Acute-on-Chronic Liver Failure.

BACKGROUND: It was postulated that CD163 plasma level should be incorporated into existing predictive systems to improve prognostic performance in patients with acute-on-chronic liver failure (ACLF). PATIENTS AND METHODS: Plasma CD163 was assessed in 24 consecutive patients with ACLF (17 male, 7 female; mean age 54.9 years; 50% with alcohol-related liver disease) and compered with the existing scoring tools to predict the availability of transplantation or survival without liver transplant (LT). RESULTS: There were no differences in plasma CD163 levels between graft recipients and deceased patients on the waiting list or transplant survivors vs nonsurvivors. CD163 did not correlate with CLIF-ACLF, CLIF Consortium organ failure score (CLIF-OF), and ACLF grades (all P < .05). However, sequential organ failure assessment (SOFA), CLIF Consortium acute-on-chronic liver failure score (CLIF-C) ACLF, and CLIF-C OF scores correlated significantly with mortality (P < .01) in contrast to Child-Pugh scale and Model for End-Stage Liver Disease score (all P > .05). Transplanted survivors and deceased individuals differed robustly with respect to the SOFA and CLIF-SOFA scores and the CLIF-C OF, CLIF-C Grade, and CLIF-C ACLF scales (all P < .05). CLIF-C performed well in ACLF prognostication with an area under receiver operating characteristic curve (AUROC) 0.893 (95% CI, 0.766-1), surpassing in that respect CD163 with AUROC of 0.664 (95% CI, 0417-0.911). CONCLUSIONS: Our preliminary results showed that the plasma CD163 level in patients with ACLF played only a minor role in predicting LT futility/benefit, with no impact on the narrow transplant window. Moreover, to optimize LT outcomes, newly developed CLIF-C scales showed superior predictive value.

Sarcopenia-The Impact on Physical Capacity of Liver Transplant Patients.

Optimizing patients' condition before liver transplantation (LT) could potentially improve survival of LT patients. We focused on sarcopenia, as a common factor in liver transplant candidates that can impact their cardiopulmonary performance at the point of listing, morbidity, and mortality after LT. We performed a single-center cohort study on 98 consecutive patients with liver cirrhosis who were transplanted between March 2015 and December 2017. The third lumbar vertebra skeletal muscle index (L3SMI) was calculated using CT imaging to distinguish sarcopenia at listing for LT. Data regarding liver function, body mass index (BMI), cardiac biomarkers, the peak oxygen uptake (VO2) and LT outcome were collected and correlated to L3SMI. For data analysis the Dell Statistica (Version 13. Dell Inc., Rondrock, TX, USA) was used. In total, 98 cirrhotic patients were included. Fifty-five (56.1%) patients, mostly males, had sarcopenia according to L3SMI, with the lowest L3SMI in males with alcohol-related liver disease. Lower L3SMI correlated with lower BMI, lower VO2 peak, and higher NTproBNP (all p < 0.001) and revealed an essential correlation with prolonged ICU stay (r = -0.21, p < 0.05). 33 patients were unable to perform cardio-pulmonary exercise test, mostly sarcopenic (67%), with more advanced liver insufficiency (assessed with CPC and MELD scores) and longer stay at ICU after LT (all p < 0.001). Sarcopenia was common among LT recipients. It was associated with inferior result in cardio-pulmonary performance before LT and prolonged ICU stay after grafting.

Genetic aspects of adult and pediatric autoimmune hepatitis: A concise review.

Autoimmune Hepatitis (AIH) is a heterogenous, mostly chronic liver disease that affects people of all age groups, women more often than men. The aim of therapy is to prevent cirrhosis, as it mainly accounts for liver-related mortality in patients with AIH. Rates of remission are high in patients with AIH, but life-long immunosuppressive therapy is required. AIH is hypothesized to originate from immunologic reactivity targeted against mostly unknown self-antigens, potentially triggered by viral infections among other factors. While AIH does not follow a Mendelian inheritance pattern, part of the risk of developing AIH or worse disease course, is attributed to specific genetic risk factors. Major associations for the risk of development of AIH were found for HLA-DRB1*03:01 and HLA-DRB1*04:01 in adult AIH in the only genome-wide association study on AIH. However, other potential risk loci in SH2B3, CARD10 and KIR genes were described. This review covers the current knowledge on genetic risk factors in adult and pediatric AIH.