De Novo Metabolic Syndrome 1 Year after Liver Transplantation and Its Association with Mid- and Long-Term Morbidity and Mortality in Liver Recipients.

Background: Metabolic syndrome (MS) constitutes an important source of cardiovascular- and cancer-related morbidity and mortality in the general population. Limited information is available on whether these findings can be directly extrapolated to liver recipients. This study aimed to investigate the impact of post-transplant MS present 1 year after liver transplantation on survival rates, risk of major cardiovascular events (CVEs), and de novo malignancies. Methods: Adult deceased-liver-donor recipients who underwent transplantation in our centre between 2010 and 2019 and reached at least 1 year of post-transplantation follow-up were eligible. Results: Of 259 enrolled patients, 20% developed post-transplant MS 1 year after the procedure. The presence of post-transplant MS at 1 year did not affect all-cause mortality (p = 0.144) and risk of de novo malignancies (p = 0.198) in liver recipients. However, it was associated with an overall and time-dependent increase in the risk of major CVEs (p < 0.001). MASH aetiology of liver disease, pre-existing major CVEs, and development of de novo malignancy were independent predictors of all-cause mortality in liver recipients. Conclusions: New onset MS exerts a wide-ranging effect on the post-transplant prognosis of liver recipients. Obtaining optimal control over all modifiable metabolic risk factors is central to improving long-term outcomes in this population.

MASH Continues as a Significant Burden on Metabolic Health of Liver Recipients.

BACKGROUND: Metabolic complications are a recognized health concern in liver transplant recipients that result in inferior patient-reported outcomes. Patients with MASH are known to be disproportionately affected by metabolic diseases compared to other indications for transplantation. PURPOSE: The aim of this study was to investigate the incidence of metabolic abnormalities in liver recipients with specific focus on differences between patients transplanted for MASH and non-MASH-causes. PATIENTS AND METHODS: An observational, monocentric, and retrospective analysis was performed. Patients who received a cadaveric-donor-liver transplant between 2010 and 2019 were eligible. RESULTS: 282 patients were enrolled with a median age of 52 years (66.7% males). Metabolic dysfunction-associated steatohepatitis (MASH) led to liver transplant in 8.2% of cases. De-novo metabolic syndrome was diagnosed in 36% of the study population. Patients that underwent transplant owing to MASH showed significantly higher incidence of metabolic complications in both pre- and post-transplant period. Considerable differences were noted in the pattern of weight gain between patients transplanted for MASH and non-MASH patients. The MASH etiology (OR: 5.5; 95% CI: 1.624-22.868; P = .010), higher BMI at 1-year post-transplant (OR: 1.321; 95% CI: 1.214-1.449; P = <.001), and older age at transplant (OR: 1.038; 95% CI: 1.006-1.074; P = .022) were independently associated with new-onset metabolic syndrome in liver recipients. CONCLUSION: Metabolic complications were prevalent in liver recipients. Liver recipients with underlying MASH significantly surpassed patients transplanted for other indications in terms of metabolic complications incidence and demonstrated an unfavorable trajectory of weight gain post-transplant.

Global Elimination of HCV-Why Is Poland Still So Far from the Goal?

INTRODUCTION: Eradication of HCV in the global population remains one of the greatest challenges faced by the WHO. An insufficient level of knowledge and the lack of a national screening test strategy are obstacles to HCV eradication. AIM: This work aimed to summarize surveys assessing risk factors and awareness of the respondents regarding the prevention and course of HCV infection. The summary also includes the most important European and global attempts at eliminating HCV. MATERIALS AND METHODS: A cross-sectional, population-based study was conducted in the Mazowieckie district in Poland using anonymous surveys and conducted on people who willingly reported for a test. RESULTS: In the study cohort of n = 7397 adults, there were 5412 women (73.16%). The analysis of the quota sample (n = 1303) reflected the actual proportions in the population of the Mazowieckie Voivodeship. CONCLUSIONS: Insufficient knowledge about HCV decreases the probability of higher detection of infections, fast diagnostics, and treatment. According to the WHO model, assuming a 90% detection rate and treatment of 80% of infected by 2030, and taking into account 120-150 thousand infected persons in Poland, the number of detections of HCV should be increased 4-5 times and all diagnosed persons should be offered antiviral treatment.

Evaluation of Long-Term Outcomes of Direct Acting Antiviral Agents in Chronic Kidney Disease Subjects: A Single Center Cohort Study.

BACKGROUND: The chronic kidney disease (CKD) population, including kidney transplant recipients (KTRs) and subjects on renal replacement therapy, is particularly vulnerable to unfavorable outcomes from chronic hepatitis C (CHC). Currently, there are oral direct-acting antiviral agents (DAAs) available to eradicate the virus with favorable short-term outcomes; however, their long-term effects are lacking. The aim of the study is to assess the long-term efficacy and safety of DAA therapy in the CKD population. METHODS: An observational, cohort single-center study was performed. Fifty-nine CHC subjects with CKD, treated with DAAs between 2016 and 2018, were enrolled in the study. Safety and efficacy profiles were assessed, including sustained virologic response (SVR), occult hepatitis C infection (OCI) incidence, and liver fibrosis. RESULTS: SVR was achieved in 96% of cases (n = 57). OCI was diagnosed only in one subject following SVR. Significant liver stiffness regression was observed 4 years after SVR compared to baseline values (Mdn = 6.1 kPa, IQR = 3.75 kPa; 4.9 kPa, IQR = 2.9 kPa), p < 0.001. The most common adverse events were anemia, weakness, and urinary tract infection. CONCLUSION: DAAs provide a safe and effective cure for CHC in both CKD patients and KTRs with a favorable safety profile in the long-term follow-up.

Are We on the Right Track for HCV Micro-Elimination? HCV Management Practices in Dialysis Centers in Poland-A National Cross-Sectional Survey.

Chronic hepatitis C (CHC) is prevalent in the hemodialysis-dependent population. Currently, all patients with CHC should be considered for treatment; however, many hemodialysis-dependent patients are still left untreated. Following HCV cure, accurate surveillance is mandatory to reduce liver-related mortality and prevent reinfection. We aimed to establish HCV management practices and barriers to HCV elimination in dialysis centers in Poland. Polish dialysis centers were surveyed via email. The HCV management strategies were investigated. Representatives of 112 dialysis centers responded, representing 43.1% of all dialysis centers in Poland and 43.4% of hemodialysis-dependent patients' volume. Most respondents were Heads of hemodialysis centers and board-certified nephrologists. The study demonstrated that in the vast majority of hemodialysis centers (91.6%), subjects are considered for antiviral treatment (AVT); however, many obstacles preventing patients from being prescribed AVT were identified; patients' reluctance to undergo AVT was most reported (60%). The majority of dialysis units neither evaluate patients with CHC for liver fibrosis (60.4%) nor screen them for hepatocellular carcinoma (53.5%). In conclusion, the presented study demonstrates that HCV management practices across Polish dialysis centers vary substantially. There is a need to optimize and streamline the HCV management infrastructure in the hemodialysis population in Poland.

Does Intrauterine Exposure of the Foetus to Immunosuppressive Drugs Used by the Mother-The Organ Recipient-Affect the Development of Post-Vaccination Immunity against Selected Viral Diseases in Children of These Mothers in Postnatal Life?

BACKGROUND: Pregnancy in women who are organ recipients has long been a controversial issue due to the lack of data on the safety of immunosuppressive drugs for the developing foetus. Scientific data show that the effect of immunosuppressants on the foetus causes an impairment of T and B lymphocyte function and a reduction in their total number. For this reason, some authors recommend delaying the obligatory immunization of infants. The aim of the study is to analyse the impact of chronic immunosuppressive therapy used during pregnancy by women after organ transplantation on the effectiveness of anti-viral vaccinations in the children of these women. METHODS: Concentrations of post-vaccination IgG antibodies (measles, HBV, polio) in 18 children of post-transplant mothers (9KTRs; 9LTRs) were determined using the ELISA method. The results were compared with the control group (n = 21). The incidence of vaccination AEs was also analysed. RESULTS: There were no significant differences between the analysed groups in the concentrations of antibodies against HBV, measles and polio (p > 0.05). CONCLUSIONS: No difference was observed in the immunogenicity of HBV, polio and measles vaccinations between children of post-transplant mothers and the general population. The immunization of children of post-transplant mothers is safe, and the percentage of adverse post-vaccination events does not differ from the general population. The obtained study results do not indicate the necessity for modifying the vaccination program for HBV, measles, and polio in this group of patients.

Rescue Therapy after Failure of HCV Antiviral Treatment with Interferon-Free Regimens.

Direct-acting antivirals (DAA) regimens have provided hope for eliminating hepatitis C virus (HCV) infection. Patients following ineffective therapy with DAA, especially those previously treated with inhibitors of non-structural protein 5A (NS5A), remain a challenge. The study aimed to assess the effectiveness of DAA pangenotypic options in patients after failure of NS5A containing genotype-specific regimens. The analysis included 120 patients selected from the EpiTer-2 database with data on 15675 HCV-infected individuals treated with IFN-free therapies from 1 July 2015 to 30 June 2022 at 22 Polish hepatology centres. The majority of them were infected with genotype (GT) 1b (85.8%) and one-third was diagnosed with fibrosis F4. Among the rescue pangenotypic regimens, the most commonly used was the sofosbuvir/velpatasvir (SOF/VEL) ± ribavirin (RBV) combination. The sustained virologic response, which was a measure of treatment effectiveness, was achieved by 102 patients, resulting in cure rate of 90.3% in the per protocol analysis. All 11 non-responders were infected with GT1b, 7 were diagnosed with cirrhosis, and 9 were treated with SOF/VEL±RBV. We demonstrated the high effectiveness of the pangenotypic rescue options in patients after genotype specific NS5A-containing regimens failures, identifying cirrhosis as a negative prognostic factor of treatment effectiveness.

Efficacy of 8- versus 12-week treatment with ledipasvir/sofosbuvir in chronic hepatitis C patients eligible for 8-week regimen in a real-world setting.

Introduction: Non-cirrhotic treatment-naive hepatitis C patients infected with genotype 1 can be treated with ledipasvir/sofosbuvir (LDV/SOF) for 8 weeks, but in practice this regimen is frequently extended up to 12 weeks at least in part due to insufficient real-world data supporting shortening of treatment. The aim of our study was to compare 8- and 12-week regimens' efficacy in patients eligible for 8-week therapy in a real-world setting. Material and methods: Data of HCV genotype 1 infected patients treated with LDV/SOF between 2015 and 2018 included in the EpiTer-2 database were analyzed with respect to patients' characteristics and length of treatment. Results: Among a total of 1718 patients treated with LDV/SOF, 679 were included in the analysis, 238 (35%) received 8-week regimen, whereas 441 were treated for 12 weeks although they fulfilled the criteria for a shorter course. The majority of patients were infected with genotype 1b (89%) and demonstrated minimal fibrosis (55%). The 12-week regimen was assigned significantly more frequently to patients with comorbidities, concomitant medications and advanced liver fibrosis. The sustained virologic response rate was similar after 8 (98%) and 12 (97%) weeks of therapy according to intent-to-treat analysis and reached 99% in both groups after exclusion of patients lost to follow-up. Conclusions: We confirmed high effectiveness regardless of treatment duration with LDV/SOF in non-cirrhotics infected with HCV genotype 1 eligible for the 8-week regimen according to the current label. This real-world study also demonstrated no need for addition of ribavirin (RBV) in this population and showed that shortening of treatment significantly improves the safety profile of LDV/SOF medication.

Molnupiravir Outpatient Treatment for Adults with COVID-19 in a Real-World Setting-A Single Center Experience.

BACKGROUND: Molnupiravir is approved for the treatment of adult patients with mild to moderate COVID-19. The main goal of the treatment is to reduce hospitalization and mortality rate. This study aimed at the all-cause hospitalization and all-cause death assessment in patients at high risk of severe COVID-19 treated with molnupiravir. METHODS: This was a prospective, observational single center study. Non-hospitalized patients with SARS-CoV-2 infection, COVID-19 symptoms with the onset of up to 5 days, and at high risk of severe COVID-19 illness received molnupiravir based on attending physician decisions. RESULTS: In total, 107 patients were enrolled. Adverse events were reported in 28.0% of patients, with nausea and abdominal pain being the most commonly observed. No treatment-emergent AEs resulted in therapy discontinuation. Overall, 15 patients required hospitalization. During the observation, 2.8% (n = 3) of patients subsequently died. All deaths were considered to be related to COVID-19 complications. Age over 65 years, heart failure, and ischemic heart disease showed a significant correlation with the severe course of COVID-19. CONCLUSION: Molnupiravir may be perceived as an alternative treatment for patients with immunosuppression and advanced chronic kidney disease. Nevertheless, further studies are required to conclusively establish a role for molnupiravir in future COVID-19 treatment recommendations.

Hepatitis C Infection as a Risk Factor for Hypertension and Cardiovascular Diseases: An EpiTer Multicenter Study.

Hepatitis C infection is one of the main reasons for liver cirrhosis and hepatocellular carcinoma. In recent years, more and more is being heard about extrahepatic manifestations of the hepatitis C infection including its possible influence on the development of hypertension and cardiovascular diseases. In the given work, the frequency analysis of the incidence of hypertension and cardiovascular diseases among 2898 HCV-infected patients treated in Poland and the assessment of their relevance to the HCV genotype and the progression of liver fibrosis can be found. The prevalence of hypertension in the group of analyzed patients was 39% and was significantly associated with old age (OR = 1.08 (1.07-1.08)) and female sex, as well as the progression of liver fibrosis (OR = 1.54 (1.29-1.85)). Hypertension was found in 47.6% of patients with F4 fibrosis, 42.1% of patients with F3 fibrosis, and 25% of patients with F1 fibrosis. The incidence of cardiovascular disease in the studied group of patients was as follows: all incidents, 131 (4.52%); including ischemic heart disease 104, (3.95%); stroke, 2 (0.07%); atherosclerosis, 21 (0.72%); and aneurysms, 4 (0.14%). The obtained results prove that the prevalence of cardiovascular diseases is significantly associated with the advanced age of patients and the progression of liver fibrosis. The relevance of sex and the HCV genotype to the prevalence frequency of cardiovascular diseases in the study group has not been proven. This being the case, no differences in the frequency of their incidence depending on the HCV genotype, including genotype 3, was found. Hepatitis C infection as a non-classical risk factor for cardiovascular disease and hypertension does require further studying.

A Review of Humoral and Cellular Immune Responses to SARS-CoV-2 Vaccination Following Solid Organ Transplantation.

The introduction of vaccines preventing a severe course of COVID-19 disease is particularly important in immunocompromised patients, among whom organ recipients and patients awaiting transplantation constitute a large group. The article is a critical review of 68 recent publications on the impact of the SARS-CoV-2 pandemic on transplantology worldwide. The study discusses research results concerning various aspects of SARS-CoV-2 vaccination in transplant patients; it also lists important factors influencing vaccination effectiveness. A suboptimal immune response to 2 doses of vaccine in this group of patients is a major challenge prompting further research. Therefore, this review aims to provide an update on the humoral and cellular immune responses to SARS-CoV-2 vaccination following solid organ transplantation.

Real-world experience with molnupiravir during the period of SARS-CoV-2 Omicron variant dominance.

BACKGROUND: The real-world effectiveness of molnupiravir (MOL) during the dominance of Omicron SARS-CoV-2 lineage is urgently needed since the available data relate to the period of circulation of other viral variants. Therefore, this study assessed the efficacy of MOL in patients hospitalized for COVID-19 in a real-world clinical practice during the wave of Omicron infections. METHODS: Among 11,822 patients hospitalized after 1 March 2020 and included in the SARSTer national database, 590 were treated between 1 January and 30 April 2022, a period of dominance of the Omicron SARS-CoV-2 variant. MOL was administered to 203 patients, whereas 387 did not receive any antiviral regimen. Both groups were similar in terms of sex, BMI and age allowing for direct comparisons. RESULTS: Patients who did not receive antiviral therapy significantly more often required the use of Dexamethasone and Baricitinib. Treatment with MOL resulted in a statistically significant reduction in mortality during the 28-day follow-up (9.9 vs. 16.3%), which was particularly evident in the population of patients over 80 years of age treated in the first 5 days of the disease (14.6 vs. 35.2%). MOL therapy did not affect the frequency of the need for mechanical ventilation, but patients treated with MOL required oxygen supplementation less frequently than those without antivirals (31.7 vs. 49.2%). The time of hospitalization did not differ between groups. CONCLUSIONS: The use of molnupiravir in patients hospitalized for COVID-19 during the dominance of Omicron variant reduced mortality. This effect is particularly evident in patients over 80 years of age.

Noninvasive Diagnostic Methods for the Assessment of Hepatic Fibrosis in Liver Transplant Recipients.

BACKGROUND: Hepatic fibrosis in liver transplant recipients is the main predictive factor for graft function. Diagnostic methods for hepatic fibrosis staging should be available, reproducible, and noninvasive, if possible. We aimed to compare diagnostic methods for the assessment of hepatic fibrosis in transplant recipients: liver biopsy as a reference method, dynamic elastography, and direct and indirect blood markers (the ELF test [Enhanced Liver Fibrosis] test and the FibroTest). We sought to set a cutoff value for each method in order to assess significant liver fibrosis (F ≥2). METHODS: The study involved 62 patients after liver transplantation. Fibrosis was assessed in biopsy specimens using the METAVIR Score System (F0-F4). To identify clinically significant cutoff values of hepatic fibrosis (F ≥2, F ≥3, F = 4) for each method compared, a receiver-operating characteristic (ROC) curve analysis was used. RESULTS: Area under ROC for the prediction of significant fibrosis (F ≥2), advanced fibrosis (F ≥3), and cirrhosis (F = 4) for the study group was 0.5938, 0.8952, and 0.9583 for dynamic elastography; 0.7295, 0.7072, and 0.8409 for the ELF test; and 0.4863, 0.8049, and 0.8723 for the FibroTest. The cutoff value for F ≥2 for dynamic elastography was 4.65 kPa; for the ELF test, 9.27; and for the FibroTest, 0.72. CONCLUSIONS: The sensitivity and specificity of the tests studied, as compared with biopsy results, increase with increasing severity of hepatic fibrosis. The noninvasive diagnostic methods are of limited value in the diagnosis of early fibrosis stages. In the diagnostic assessment of hepatic fibrosis in its advanced stages, dynamic elastography can be used in conjunction with ELF test as a noninvasive alternative to liver biopsy.

Utilization of HCV viremic donors in kidney transplantation: a chance or a threat?

Kidney transplantation is the treatment of choice in end-stage renal disease. The main issue which does not allow to utilize it fully is the number of organs available for transplant. Introduction of highly effective oral direct-acting antivirals (DAAs) to the treatment of chronic hepatitis C virus infection (HCV) enabled transplantation of HCV viremic organs to naive recipients. Despite an increasing number of reports on the satisfying effects of using HCV viremic organs, including kidneys, they are more often rejected than those from HCV negative donors. The main reason is the presence of HCV viremia and not the quality of the organ. The current state of knowledge points to the fact that a kidney transplant from an HCV nucleic acid testing positive (NAT+) donor to naive recipients is an effective and safe solution to the problem of the insufficient number of organs available for transplantation. It does not, however, allow to draw conclusions as to the long-term consequence of such an approach. This review analyzes the possibilities and limitations of the usage of HCV NAT + donor organs. Abbreviations: DAA: direct-acting antivirals; HCV: hepatitis C virus; NAT: nucleic acid testing; OPTN: Organ Procurement and Transplantation Network; KDIGO: Kidney Disease: Improving Global Outcomes; Ab: antigen; eGFR: estimated glomerular filtration rate; D: donor; R: recipient; CMV: cytomegalovirus; HBV: hepatitis B virus; UNOS: United Network for Organ Sharing; PHS: Public Health Service; EBR/GZR: elbasvir/grazoprevir; SVR: sustained virologic response; RAS: resistance-associated substitutions; SOF: soforbuvir; GLE/PIB: glecaprevir/pibrentasvir; ACR: acute cellular rejection; AR: acute rejection; DSA: donor-specific antibodies; KTR: kidney transplant recipients; AASLD: American Association for the Study of Liver Disease; IDSA: Infectious Diseases Society of America; PPI: proton pump inhibitors; CKD: chronic kidney disease; GN: glomerulonephritis; KAS: The Kidney Allocation system.

HCV Genotype Has No Influence on the Incidence of Diabetes-EpiTer Multicentre Study.

HCV infection is one of the main reasons for liver cirrhosis and hepatocellular carcinoma. In recent years, one finds more and more extrahepatic manifestations of HCV infection, including its possible influence on the development of diabetes. In the presented work, one finds the frequency analysis of the incidence of diabetes among 2898 HCV infected patients treated in Poland, and the assessment of their relevance to the HCV genotype and the progression of fibrosis. The results indicate that the hepatitis C infection seems to be a risk factor for diabetes in persons with more advanced liver fibrosis, for older people, and for the male gender. Thus, one found no differences regarding the frequency of its incidence depending on HCV genotype, including genotype 3.

Pangenotypic and Genotype-Specific Antivirals in the Treatment of HCV Genotype 4 Infected Patients with HCV Monoinfection and HIV/HCV Coinfection.

The introduction of the direct-acting antivirals (DAA) has substantially improved the effectiveness of the therapy in patients with chronic hepatitis C. We aimed to compare the efficacy of pangenotypic and genotype-specific DAA in the cohort of genotype (GT) four patients with HCV monoinfection and HIV coinfection. A total of 662 GT4-infected patients treated in 2015-2020-of whom 168 (25.3%) were coinfected with HIV, selected from the retrospective EpiTer-2 database-were enrolled in the analysis. Among HIV-coinfected patients, 54% (90) were treated with genotype-specific regimens and 46% (78) with pangenotypic options, while among HCV-monoinfected patients, the rates were 72% and 28%, respectively. Significantly higher rate of males (67.9% vs. 57.7%, p = 0.01), a lower rate of liver cirrhosis (10.2% vs. 18.1%, p = 0.02), and higher of treatment-naïve patients (87.5% vs. 76.7%, p = 0.003) were documented in the HIV coinfected population. The overall sustained virologic response after exclusion of non-virologic failures was achieved in 98% with no significant difference between HIV-positive and HIV-negative patients, 96.2% vs. 98.5%, respectively. While the genotype-specific regimens resulted in a similar cure rate regardless of the HIV status, the pangenotypic options were more efficacious in patients with HCV monoinfection (99.3% vs. 94.4%, p = 0.05). Hereby, we demonstrated the high effectiveness and good safety profile of the DAA therapy in the population of HCV GT4 infected patients with HIV coinfection supporting the current recommendations to treat HCV/HIV coinfected patients with the same options as those with HCV monoinfection.

Recurrence of Hepatocellular Carcinoma After Liver Transplantation: Risk Factors and Predictive Models.

Liver transplantation (LTx) is the best treatment for patients with early-stage hepatocellular carcinoma (HCC). The Milan criteria positively influenced results of liver transplantation and were adopted by the majority of cancer centers, becoming the criterion standard treatment for early-stage HCC. Despite the use of restrictive criteria, recurrence is still high, affecting between 8% and 20% of cases, and is a significant predictor of survival after LTx. The diagnosis of both micro-and macro-invasion of vessels, which are significant factors in determining the frequency of recurrence and overall survival, significantly decreases the success of transplantation, causing an increase in mortality of 50% in comparison to recipients with no vascular invasion. The risk of recurrence depends on several factors, which are discussed in this review. The authors also discuss the clinical presentation and treatment methods of recurrence and its prognosis. In addition, the role of different models developed to identify groups of patients with high versus low risk of recurrence is discussed, enabling the planning of recommendations and screening protocols after transplantation to help early diagnosis and guide effective treatment. In the era of an increasing numbers of liver transplants due to HCC, the need to create robust screening tools is urgent.

Multidirectional facets of obesity management in the metabolic syndrome population after liver transplantation.

The obesity pandemic has resulted in an increasing demand for liver transplantation and has significantly altered the profile of liver transplant candidates in addition to affecting posttransplantation outcomes. In this review, we discuss a broad range of clinical approaches that warrant attention to provide comprehensive and patient-centred medical care to liver transplant recipients, and to be prepared to confront the rapidly changing clinical challenges and ensuing dilemmas. Adipose tissue is a complex and metabolically active organ. Visceral fat deposition is a key predictor of overall obesity-related morbidity and mortality. Limited pharmacological options are available for the treatment of obesity in the liver transplant population. Bariatric surgery may be an alternative in eligible patients. The rapidly increasing prevalence of nonalcoholic fatty liver disease (NAFLD) is a global concern; NAFLD affects both pre- and posttransplantation outcomes. Numerous studies have investigated pharmacological and nonpharmacological management of NAFLD and some of these have shown promising results. Liver transplant recipients are constantly exposed to numerous factors that result in intestinal microbiota alterations, which were linked to the development of obesity, diabetes type 2, metabolic syndrome (MS), NAFLD, and hepatocellular cancer. Microbiota modifications with probiotics and prebiotics bring gratifying results in the management of metabolic complications. Fecal microbiota transplantation (FMT) is successfully performed in many medical indications. However, the safety and efficacy profiles of FMT in immunocompromised patients remain unclear. Obesity together with immunosuppressive treatment, may affect the pharmacokinetic and/or pharmacodynamic properties of coadministered medications. Individualized immunosuppressive regimens are recommended following liver transplantation to address possible metabolic concerns. Effective and comprehensive management of metabolic complications is shown to yield multiple beneficial results in the liver transplant population and may bring gratifying results in improving long-term survival rates.

The molecular phenotypes of injury, steatohepatitis, and fibrosis in liver transplant biopsies in the INTERLIVER study.

To extend previous molecular analyses of rejection in liver transplant biopsies in the INTERLIVER study (ClinicalTrials.gov #NCT03193151), the present study aimed to define the gene expression selective for parenchymal injury, fibrosis, and steatohepatitis. We analyzed genome-wide microarray measurements from 337 liver transplant biopsies from 13 centers. We examined expression of genes previously annotated as increased in injury and fibrosis using principal component analysis (PCA). PC1 reflected parenchymal injury and related inflammation in the early posttransplant period, slowly regressing over many months. PC2 separated early injury from late fibrosis. Positive PC3 identified a distinct mildly inflamed state correlating with histologic steatohepatitis. Injury PCs correlated with liver function and histologic abnormalities. A classifier trained on histologic steatohepatitis predicted histologic steatohepatitis with cross-validated AUC = 0.83, and was associated with pathways reflecting metabolic abnormalities distinct from fibrosis. PC2 predicted histologic fibrosis (AUC = 0.80), as did a molecular fibrosis classifier (AUC = 0.74). The fibrosis classifier correlated with matrix remodeling pathways with minimal overlap with those selective for steatohepatitis, although some biopsies had both. Genome-wide assessment of liver transplant biopsies can not only detect molecular changes induced by rejection but also those correlating with parenchymal injury, steatohepatitis, and fibrosis, offering potential insights into disease mechanisms for primary diseases.