A DNA methylation atlas of normal human cell types.

DNA methylation is a fundamental epigenetic mark that governs gene expression and chromatin organization, thus providing a window into cellular identity and developmental processes1. Current datasets typically include only a fraction of methylation sites and are often based either on cell lines that underwent massive changes in culture or on tissues containing unspecified mixtures of cells2-5. Here we describe a human methylome atlas, based on deep whole-genome bisulfite sequencing, allowing fragment-level analysis across thousands of unique markers for 39 cell types sorted from 205 healthy tissue samples. Replicates of the same cell type are more than 99.5% identical, demonstrating the robustness of cell identity programmes to environmental perturbation. Unsupervised clustering of the atlas recapitulates key elements of tissue ontogeny and identifies methylation patterns retained since embryonic development. Loci uniquely unmethylated in an individual cell type often reside in transcriptional enhancers and contain DNA binding sites for tissue-specific transcriptional regulators. Uniquely hypermethylated loci are rare and are enriched for CpG islands, Polycomb targets and CTCF binding sites, suggesting a new role in shaping cell-type-specific chromatin looping. The atlas provides an essential resource for study of gene regulation and disease-associated genetic variants, and a wealth of potential tissue-specific biomarkers for use in liquid biopsies.

An ethical analysis of conditional and partially directed live kidney donation among strangers-The Israeli experience.

Living donor kidney transplantation (LDKT) is one of the most effective treatment options for people with end-stage renal disease. Traditionally, LDKT can be either "directed" or "nondirected," based on whether the recipient is specified by the donor. Recently, there has been an increase in conditional and semidirected live kidney donation among strangers, where the donor specifies the characteristics of the recipient whom they wish to donate to. This practice has both gained popularity and sparked controversy in the state of Israel through the nonprofit organization Matnat Chaim. We analyze the ethical implications of this practice by applying traditional principles of medical ethics to conditional LDKT. Although semidirected and conditional LDKT presents some ethical challenges, overall, its practice effectively aligns with core ethical principles. The donors' right to make stipulations respects the donor's autonomy, the practice avoids harm and benefits both donor and recipient, and justice and utility are upheld as the practice specifically benefits marginalized patients and optimizes resource utilization. Finally, we present data from our institution demonstrating how conditional LDKT increased transplantation for all ethnic groups; Jewish recipients of LDKT increased by 151.32% (P = .034) Arab recipients of LDKT increased by 111.11% (P = .036).

Distinct Murine Mucosal Langerhans Cell Subsets Develop from Pre-dendritic Cells and Monocytes.

Langerhans cells (LCs) populate the mucosal epithelium, a major entry portal for pathogens, yet their ontogeny remains unclear. We found that, in contrast to skin LCs originating from self-renewing radioresistant embryonic precursors, oral mucosal LCs derive from circulating radiosensitive precursors. Mucosal LCs can be segregated into CD103(+)CD11b(lo) (CD103(+)) and CD11b(+)CD103(-) (CD11b(+)) subsets. We further demonstrated that similar to non-lymphoid dendritic cells (DCs), CD103(+) LCs originate from pre-DCs, whereas CD11b(+) LCs differentiate from both pre-DCs and monocytic precursors. Despite this ontogenetic discrepancy between skin and mucosal LCs, the transcriptomic signature and immunological function of oral LCs highly resemble those of skin LCs but not DCs. These findings, along with the epithelial position, morphology, and expression of the LC-associated phenotype strongly suggest that oral mucosal LCs are genuine LCs. Collectively, in a tissue-dependent manner, murine LCs differentiate from at least three distinct precursors (embryonic, pre-DC, and monocytic) in steady state.

Mutual interplay between IL-17-producing γδT cells and microbiota orchestrates oral mucosal homeostasis.

γδT cells are a major component of epithelial tissues and play a role in tissue homeostasis and host defense. γδT cells also reside in the gingiva, an oral tissue covered with specialized epithelium that continuously monitors the challenging dental biofilm. Whereas most research on intraepithelial γδT cells focuses on the skin and intestine epithelia, our knowledge on these cells in the gingiva is still incomplete. In this study, we demonstrate that even though the gingiva develops after birth, the majority of gingival γδT cells are fetal thymus-derived Vγ6+ cells, and to a lesser extent Vγ1+ and Vγ4+ cells. Furthermore, we show that γδT cells are motile and locate preferentially in the epithelium adjacent to the biofilm. Vγ6+ cells represent the major source of IL-17-producing cells in the gingiva. Chimeric mice and parabiosis experiments indicated that the main fraction of gingival γδT cells is radioresistant and tissue-resident, persisting locally independent of circulating γδT cells. Notably, gingival γδT cell homeostasis is regulated by the microbiota as the ratio of Vγ6+ and Vγ4+ cells was reversed in germ-free mice, and their activation state was decreased. As a consequence, conditional ablation of γδT cells results in elevated gingival inflammation and subsequent alterations of oral microbial diversity. Taken together, these findings suggest that oral mucosal homeostasis is shaped by reciprocal interplays between γδT cells and local microbiota.

The impact of preoperative vitamin administration on skeletal status following sleeve gastrectomy in young and middle-aged women: a randomized controlled trial.

BACKGROUND: The appropriate strategies to minimize skeletal deterioration following bariatric surgeries are inconclusive. This randomized controlled trial evaluated the effect of preoperative vitamin supplementation on bone mineral density (BMD) and biochemical parameters in females post-sleeve gastrectomy (SG). METHODS: Participants were randomized to a 2-month preoperative treatment with a multivitamin and vitamin D 4000 IU/d (intervention arm) or 1200 IU/d (control arm). Preoperative and 12-month postoperative follow-up evaluations included anthropometrics, biochemical parameters, and dual energy X-ray absorptiometry (DEXA). RESULTS: Sixty-two females (median age 29.7 years and median BMI 43.4 kg/m2) were recruited, 87% completed the 12-month follow-up. For the intervention and control arms, significant and similar reductions at 12-months post-surgery were observed in BMD of the hip (-6.8 ± 3.7% vs. -6.0 ± 3.6%; P = 0.646) and of the femoral neck (-7.1 ± 5.8% vs. -7.2 ± 5.5%; P = 0.973). For the intervention compared to the control arm, the 25 hydroxyvitamin D (25(OH)D) increment was greater after 2 months treatment, and vitamin D deficiency rates were lower at 3 and 6-months follow-up (P < 0.016). However, at 12-months postoperative, 25(OH)D values and vitamin D deficiency were comparable between the arms (P > 0.339). Predictors for BMD decline in the total hip were the percentage of excess weight-loss, age>50 years, and lower initial BMI (P ≤ 0.003). CONCLUSIONS: SG was associated with a significant decline in BMD of the hip and femoral neck in young and middle-aged women, and was unaffected by preoperative vitamin D supplementation. Females who are peri-menopausal or with greater postoperative weight-loss should be particularly followed for BMD decline.

Splenic Vein as an Autologous Graft in Traumatic SMV Injuries: A Missed Valuable Alternative.

Traumatic superior mesenteric artery (SMA) and vein (SMV) injuries are rare but often lethal. The ideal management options of traumatic SMV injury are still controversial. Management options include venous repair and ligation. Splenic vein turndown procedure (SVTP) is a rare procedure that has been described in only 6 cases in the literature. Here, we reviewed the literature on the usage of the splenic vein turndown procedure (SVTP) as an alternative option in patients with traumatic SMV injury. METHODS: We performed a narrative review for the available literature on the usage of the splenic vein as an autologous graft in the management of the SMV injury. We included all studies of SVTP in traumatic SMV injuries only. RESULTS: We included only 5 studies. In total, 7 patients underwent SVTP. Five patients presented with a penetrating abdominal vascular trauma (AVT) and 2 patients with a blunt AVT. The advantages of the SVTP include no need for additional incisions to harvest potential autologous grafts, minimally increased operative time, and 1 less anastomotic site compared to other conduit options. CONCLUSIONS: In cases of traumatic SMV injuries with associated splenic or pancreatic injuries that need distal pancreatosplenectomy, surgeons may consider SVTP as an ideal management option rather than primary repair or ligation.

VHL-Related Neuroendocrine Neoplasms And Beyond: An Israeli Specialized Center Real-Life Report.

OBJECTIVE: Von Hippel-Lindau (VHL) syndrome is a rare and complex disease. In 1996, we described a 3 generation VHL 2A kindred with 11 mutation carriers. We aim to share our experience regarding the long-term follow-up of this family and the management of all our other VHL patients focusing on frequently encountered neuroendocrine neoplasms: pheochromocytoma/paraganglioma and pancreatic neuroendocrine neoplasms (PNEN). METHODS: All VHL patients in follow-up at our tertiary center from 1980 to 2019 were identified. Clinical, laboratory, imaging, and therapeutic characteristics were retrospectively analyzed. RESULTS: We identified 32 VHL patients in 16 different families, 7/16 were classified as VHL 2 subtype. In the previously described family, the 4 initially asymptomatic carriers developed a neuroendocrine tumor; 7 new children were born, 3 of them being mutation carriers; 2 patients died, 1 due to metastatic PNEN-related liver failure. Pheochromocytoma was frequent (22/32), bilateral (13/22;59%), often diagnosed in early childhood when active screening was timely performed, associated with paraganglioma in 5/22, rarely malignant (1/22), and recurred after surgery in some cases after more than 20 years. PNEN occurred in 8/32 patients (25%), and was metastatic in 3 patients. Surgery and palliative therapy allowed relatively satisfactory outcomes. Severe disabling morbidities due to central-nervous system and ophthalmologic hemangiomas, and other rare tumors as chondrosarcoma in 2 patients and polycythemia in 1 patient were observed. CONCLUSION: A multidisciplinary approach and long-term follow-up is mandatory in VHL patients to manage the multiple debilitating morbidities and delay mortality in these complex patients.

Successful Embolization of Hemorrhagic Hepatic Hydatid Cyst Followed by Surgical Resection: Report of Two Cases and Review of the Literature.

Hepatic hydatid cysts (HHCs) are common in endemic areas. Mostly they are asymptomatic, but some cause serious complications. We report 2 cases of HHC complicated arterial bleeding. Owing to signs of active bleeding, the patients were treated with selective embolization of the hepatic artery to stop the bleeding and stabilize the patients' condition. Subsequently, partial hepatectomy of the involved liver lobe was performed in an elective setting and without postoperative complications. We recommend bridging therapy by selective angiography and embolization for hemorrhagic hepatic hydatid cyst before definitive surgical treatment.

Pre-liver transplant psychosocial evaluation predicts post-transplantation outcomes.

Psychosocial factors greatly impact the course of patients throughout the liver transplantation process. A retrospective chart review was performed of patients who underwent liver transplantation at Hadassah-Hebrew University Medical Center between 2002 and 2012. A composite psychosocial score was computed based on the patient's pre-transplant evaluation. Patients were divided into two groups based on compliance, support and insight: Optimal psychosocial score and Non-optimal psychosocial score. Post-liver transplantation survival and complication rates were evaluated. Out of 100 patients who underwent liver transplantation at the Hadassah-Hebrew University Medical Center between 2002 and 2012, 93% had a complete pre-liver transplant psychosocial evaluation in the medical record performed by professional psychologists and social workers. Post-liver transplantation survival was significantly higher in the Optimal group (85%) as compared to the Non-optimal group (56%, p = .002). Post-liver transplantation rate of renal failure was significantly lower in the Optimal group. No significant differences were observed between the groups in other post-transplant complications. A patient's psychosocial status may impact outcomes following transplantation as inferior psychosocial grades were associated with lower overall survival and increased rates of complications. Pre-liver transplant psychosocial evaluations are an important tool to help predict survival following transplantation.

Outcome of bariatric surgery in patients with type 1 diabetes mellitus: our experience and review of the literature.

BACKGROUND: The beneficial effect of bariatric surgery (BS) in type 2 diabetes mellitus patients is well established. Conversely, little is known about the efficacy of BS in type 1 diabetes mellitus (T1DM) patients, despite the increasing prevalence of obesity in this population. METHODS: A retrospective review was carried out on a prospectively collected bariatric surgery registry of all patients undergoing BS at two university hospitals between 2010 and 2015. Patients with T1DM were identified, and detailed chart reviews were obtained. RESULTS: In this time period, we operated on thirteen patients with T1DM. Eight were female (61.5 %). Median age at time of surgery was 38 ± 8.3 (range 28-53) years. The procedures performed were laparoscopic sleeve gastrectomy (n = 10) and laparoscopic Roux-en-Y gastric bypass (n = 3). On median postoperative follow-up of 24 (range 2.5-51) months, mean body mass index significantly decreased from 39.9 ± 4.1 to 30.1 ± 3.9 kg/m2 (P < 0.0001) and insulin requirements were significantly reduced from 83.7 ± 40.4 to 45.7 ± 33.1 U/day (P < 0.01). However, there was no significant change in glycemic control assessed by HbA1C (P = 0.2). During the first months following surgery, three patients (21.4 %) experienced diabetic ketoacidosis, and four patients (28.6 %) reported more frequent episodes of hypoglycemia. CONCLUSIONS: Bariatric surgery in morbidly obese T1DM patients is an effective method for weight loss, leading to a remarkable improvement in insulin requirements. Larger prospective studies are still needed to confirm these findings, assess long-term effects of BS and better delineate its risk-to-benefit ratio in this growing population of morbidly obese patients with T1DM.

Mutant KRAS is a druggable target for pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDA) represents an unmet therapeutic challenge. PDA is addicted to the activity of the mutated KRAS oncogene which is considered so far an undruggable therapeutic target. We propose an approach to target KRAS effectively in patients using RNA interference. To meet this challenge, we have developed a local prolonged siRNA delivery system (Local Drug EluteR, LODER) shedding siRNA against the mutated KRAS (siG12D LODER). The siG12D LODER was assessed for its structural, release, and delivery properties in vitro and in vivo. The effect of the siG12D LODER on tumor growth was assessed in s.c. and orthotopic mouse models. KRAS silencing effect was further assessed on the KRAS downstream signaling pathway. The LODER-encapsulated siRNA was stable and active in vivo for 155 d. Treatment of PDA cells with siG12D LODER resulted in a significant decrease in KRAS levels, leading to inhibition of proliferation and epithelial-mesenchymal transition. In vivo, siG12D LODER impeded the growth of human pancreatic tumor cells and prolonged mouse survival. We report a reproducible and safe delivery platform based on a miniature biodegradable polymeric matrix, for the controlled and prolonged delivery of siRNA. This technology provides the following advantages: (i) siRNA is protected from degradation; (ii) the siRNA is slowly released locally within the tumor for prolonged periods; and (iii) the siG12D LODER elicits a therapeutic effect, thereby demonstrating that mutated KRAS is indeed a druggable target.

Short-term overexpression of VEGF-A in mouse beta cells indirectly stimulates their proliferation and protects against diabetes.

AIMS/HYPOTHESIS: Vascular endothelial growth factor (VEGF) has been recognised by loss-of-function experiments as a pleiotropic factor with importance in embryonic pancreas development and postnatal beta cell function. Chronic, nonconditional overexpression of VEGF-A has a deleterious effect on beta cell development and function. We report, for the first time, a conditional gain-of-function study to evaluate the effect of transient VEGF-A overexpression by adult pancreatic beta cells on islet vasculature and beta cell proliferation and survival, under both normal physiological and injury conditions. METHODS: In a transgenicmouse strain, overexpressing VEGF-A in a doxycycline-inducible and beta cell-specific manner, we evaluated the ability of VEGF-A to affect islet vessel density, beta cell proliferation and protection of the adult beta cell mass from toxin-induced injury. RESULTS: Short-term VEGF-A overexpression resulted in islet hypervascularisation, increased beta cell proliferation and protection from toxin-mediated beta cell death, and thereby prevented the development of hyperglycaemia. Extended overexpression of VEGF-A led to impaired glucose tolerance, elevated fasting glycaemia and a decreased beta cell mass. CONCLUSIONS/INTERPRETATION: Overexpression of VEGF-A in beta cells time-dependently affects glycometabolic control and beta cell protection and proliferation. These data nourish further studies to examine the role of controlled VEGF delivery in (pre)clinical applications aimed at protecting and/or restoring the injured beta cell mass.

Laparoscopic sleeve gastrectomy with transgastric visualization: another step toward totally NOTES procedures.

BACKGROUND: Laparoendoscopic single-site sleeve gastrectomy is gaining acceptance. However, totally natural orifice translumenal endoscopic surgery (NOTES) in morbidly obese patients is still controversial due to safety and technical issues. To this end, we have developed a technique for sleeve gastrectomy in which the surgical field view is achieved through transgastric approach and the operating channel will eventually be through the vagina to form a dual lumen totally NOTES procedure for sleeve gastrectomy. As a step toward this approach, we performed a single abdominal incision in order to simulate the transvaginal route. This study is another step toward combined transvaginal and transgastric totally NOTES sleeve gastrectomy. METHODS AND PROCEDURES: A combined NOTES and single trocar sleeve gastrectomy was performed on 8 porcine animal models. The endoscope was inserted through the gastric wall and served as the vision source for the procedure. A second endoscope was inserted via the transabdominal trocar together with the surgical instruments. RESULTS: Sleeve gastrectomy was performed on 8 porcine models. The operative time for the first procedure was 5 hours, but after determining the technique, the time was reduced by half. CONCLUSION: Combined NOTES and single trocar sleeve gastrectomy is feasible in a porcine model. We achieved an excellent view of the surgical field through the transgastric approach. We believe that in the near future, combining the transgastric visualization of the surgical field together with a transvaginal approach may enable performing a total NOTES sleeve gastrectomy procedure. This hypothesis will be studied in further animal experiments before implementation in humans.

Erratum: Removal notice to "Successful management of an Iatrogenic portal vein and hepatic artery injury in a 4-month-old female patient: A case report and literature review" [Radiology Case Reports 19 (2024) 2106-2111].

[This corrects the article DOI: 10.1016/j.radcr.2024.02.037.].

REMOVED: Successful management of an Iatrogenic portal vein and hepatic artery injury in a 4-month-old female patient: A case report and literature review.

This article has been removed: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/policies/article-withdrawal).

Role of the ductal transcription factors HNF6 and Sox9 in pancreatic acinar-to-ductal metaplasia.

OBJECTIVE: Growing evidence suggests that a phenotypic switch converting pancreatic acinar cells to duct-like cells can lead to pancreatic intraepithelial neoplasia and eventually to invasive pancreatic ductal adenocarcinoma. Histologically, the onset of this switch is characterised by the co-expression of acinar and ductal markers in acini, a lesion called acinar-to-ductal metaplasia (ADM). The transcriptional regulators required to initiate ADM are unknown, but need to be identified to characterise the regulatory networks that drive ADM. In this study, the role of the ductal transcription factors hepatocyte nuclear factor 6 (HNF6, also known as Onecut1) and SRY-related HMG box factor 9 (Sox9) in ADM was investigated. DESIGN: Expression of HNF6 and Sox9 was measured by immunostaining in normal and diseased human pancreas. The function of the factors was tested in cultured cells and in mouse models of ADM by a combination of gain and loss of function experiments. RESULTS: Expression of HNF6 and Sox9 was ectopically induced in acinar cells in human ADM as well as in mouse models of ADM. HNF6 and, to a lesser extent, Sox9 were required for repression of acinar genes, for modulation of ADM-associated changes in cell polarity and for activation of ductal genes in metaplastic acinar cells. CONCLUSIONS: HNF6 and Sox9 are new biomarkers of ADM and constitute candidate targets for preventive treatment in cases when ADM may lead to cancer. This work also shows that ectopic activation of transcription factors may underlie metaplastic processes occurring in other organs.

Effect of Age on Liver Transplantation Recipient Outcomes: Two Centers' Experience.

BACKGROUND: Liver diseases epidemiology has changed with advances in perioperative care. Transplantation at large centers is favorable among older and younger recipients. Local limitations on transplantation for recipients older than 65 years were cancelled in 2014. This study evaluates the effects of age on the transplantation outcome of Israeli patients in the era after removal of the limitations on recipient age. METHODS: This retrospective analysis examined prospective data on patients older than 18 years who underwent liver or liver-kidney transplantation between 2014 and 2019 at 2 transplantation centers. Patients were divided into 4 age groups (group 1: ≤59 years; group 2: 60-64 years; group 3: 65-69 years; and group 4: ≥70 years). Each group's associations of pretransplantation factors with outcome and survival were examined. RESULTS: Two hundred sixty-one recipients underwent 269 transplantations (mean age: 53 ± 12.61 y). There were 181 male (67.8%) and 88 female recipients (67.28%). Overall, 207 patients (79.6%) survived ≥12 months. One-year survival rates were 82.9%, 73.2%, 71.4%, and 93.8% for groups 1 to 4, respectively (not statistically significant; P = .11). One-year graft survival was similar between groups. More patients with chronic obstructive pulmonary disease, diabetes mellitus, or ischemic heart disease tended to survive <12 months. Cardiovascular complication was more common in older groups and affected survival. CONCLUSION: Patient age alone should not be used to deny access to transplantation, which could benefit older nonfrail individuals. However, risk factors such as male sex, chronic obstructive pulmonary disease, ischemic heart disease, diabetes mellitus, and concomitant kidney-liver transplantation should be carefully considered.

SARS-CoV-2 vaccine alleviates disease burden and severity in liver transplant recipients even with low antibody titers.

BACKGROUND AND AIMS: We retrospectively assessed the clinical Pfizer's mRNA SARS-CoV-2 BNT162b2 vaccination outcomes and the serologic impact on liver transplant (LT) recipients. PATIENTS AND METHODS: One hundred and sixty-seven LT cases followed between March 1, 2020 and September 25, 2021, and were stratified into two groups: (1) 37 LT recipients after SARS-CoV-2 infection before vaccine era and (2) 130 LT recipients vaccinated with 2 doses without earlier SARS-CoV-2 exposure. Serum SARS-CoV-2 spike immunoglobulins (anti-S) were assessed 7 days following vaccination (Liaison assay). RESULTS: In addition to the 37 nonvaccinated cases (22.2% of total group) who experienced SARS-CoV-2 infection (34 symptomatic and 3 asymptomatic), another 8 vaccinated symptomatic recipients (4.8%) were infected (5 from the third and three from the fourth waves). Three of the 45 infected cases died (6.7%) before the vaccine program. Vaccinated group: of the 130 LT vaccinated recipients, 8 (6.2%) got infected postvaccination (added to the infected group) and were defined as clinical vaccine failure; 38 (29.2%) were serological vaccine failure (total failure 35.4%), and 64.6% cases were serological vaccine responders (anti-S≥19 AU/mL). Longer post-LT interval and lower consumption of immunosuppressants (steroids, FK506, and mycophenolate mofetil) correlated with favorable SARS-CoV-2 vaccine response. Mammalian target of rapamycin inhibitors improved vaccine outcomes associated with lower FK506 dosages and serum levels. Patients with anti-S levels <100 AU/mL risked losing serologic response or being infected with SARS-CoV-2. A booster dose achieved an effective serologic response in a third of failures and most responders, securing better and possibly longer protection. CONCLUSION: Pfizer's BNT162b2 vaccine seems to lessen SARS-CoV-2 morbidity and mortality of LT recipients even with weak serological immunogenicity. Switching mycophenolate mofetil to mammalian target of rapamycin inhibitors might be effective before boosters in vaccine failure cases. A booster vaccine should be considered for nonresponders and low-responders after the second dose.

Weaker SARS-CoV-2 vaccine responses in nonalcoholic fatty liver disease with advanced liver fibrosis.

Background: SARS-CoV-2 vaccine responses that could harbor potential risks to chronic liver diseased patients. Aims: To assess immune response following Pfizer's SARS-CoV-2 vaccine in patients with different liver fibrosis severities of nonalcoholic fatty liver disease (NAFLD). Methods: Clinical and histological (NAS-score and fibrosis stage) characteristics of NAFLD patients before vaccine were correlated with serologic vaccine responses of two doses of the BNT162b2. Serum SARS-CoV-2 spike immunoglobulins (anti-S) were assessed on day seven following immunization (Liaison assay). Results: The mean-age of patients (n = 157) was 56.9 ± 13.2 years (46.5 % males). 94.8 % had a positive response (anti-S levels ≥ 19 AU/ml). The anti-S cutoff of 200 AU/ml used to separate strong vs. weak responses. A strong response (anti-S titers ≥ 200 AU/ml) was observed in 93/157 (59.2 %) patients with a mean-age of 53.1 ± 13.8 years (45.2 % males). A weak response (anti-S titers < 200 AU/ml) was observed in 64/157 (40.8 %) cases with a mean-age of 62.3 ± 10.2 years (p < 0.0001). The strong response subgroup had lower metabolic comorbidities, including glucose hemostasis, hypertension, and dyslipidemia (p < 0.04). Moreover, the strong response subgroup had fibrosis stages F0-F2 (75.3 % vs. 56.3 %) and lower rates of advanced stages F3-F4 (24.7 % vs. 43.8 %). The F0-F2 subgroups had significantly higher rates of strong responses than the F3-F4 stages. The anti-S ≥ 200 and anti-S ≥ 400 AU/ml response achieved in 66 % and 36.8 % of the F0-F2 population was significantly higher than the 45.1 % (p = 0.006) and 23.5 % (p = 0.05) in the F3-F4 population, respectively. The Fib-4 calculations and Fibroscan evaluations were consistent with histologic fibrosis assessment. Conclusion: Advanced liver fibrosis (assessed by histology, Fib-4, or Fibroscan) is a risk factor for lower response to Pfizer's BNT162b2 vaccine, and patients should be prioritized for the vaccine booster against SARS-CoV-2.