Targeted long-read sequencing identifies and characterizes structural variants in cases of inherited platelet disorders.

BACKGROUND: Genetic diagnosis of inherited platelet disorders (IPDs) is mainly performed by high-throughput sequencing (HTS). These short-read-based sequencing methods sometimes fail to characterize the genetics of the disease. OBJECTIVES: To evaluate nanopore long-read DNA sequencing for characterization of structural variants (SVs) in patients with IPDs. METHODS: Four patients with a clinical and laboratory diagnosis of Glanzmann thrombasthenia (GT) (P1 and P2) and Hermansky-Pudlak syndrome (HPS) (P3 and P4) in whom HTS missed the underlying molecular cause were included. DNA was analyzed by both standard HTS and nanopore sequencing on a MinION device (Oxford Nanopore Technologies) after enrichment of DNA spanning regions covering GT and HPS genes. RESULTS: In patients with GT, HTS identified only 1 heterozygous ITGB3 splice variant c.2301+1G>C in P2. In patients with HPS, a homozygous deletion in HPS5 was suspected in P3, and 2 heterozygous HPS3 variants, c.2464C>T (p.Arg822∗) and a deletion affecting 2 exons, were reported in P4. Nanopore sequencing revealed a complex SV affecting exons 2 to 6 in ITGB3 (deletion-inversion-duplication) in homozygosity in P1 and compound heterozygosity with the splice variant in P2. In the 2 patients with HPS, nanopore defined the length of the SVs, which were characterized at nucleotide resolution. This allowed the identification of repetitive Alu elements at the breakpoints and the design of specific polymerase chain reactions for family screening. CONCLUSION: The nanopore technology overcomes the limitations of standard short-read sequencing techniques in SV characterization. Using nanopore, we characterized novel defects in ITGB3, HPS5, and HPS3, highlighting the utility of long-read sequencing as an additional diagnostic tool in IPDs.

Long-term clinical and socioeconomic outcomes of children with biliary atresia.

Background: Biliary atresia (BA) is rare liver disease of unknown etiology, and is a major indication for liver transplant (LT). Previous data indicate improved outcomes with early referral for Kasai portoenterostomy (KPE). Objective: Evaluate the long-term outcomes in BA, with particular focus on those transitioned to adult care with native livers. Subjects and Methods: Patients with BA treated between1980 and 2012 were identified. Data were collected from the time of referral, transition to adult care, and the most recent clinic notes, from which patient and native liver survival were calculated. Results: Four hundred and fifty-four patients with BA were identified, who were followed up for median of 16.4 years from birth; 74 died (41 of whom had a LT), giving a 20-year survival rate of 83.6%. Two hundred and seventy-two patients received an LT, with the median native liver survival being 35 months. Of patients who transitioned to adult care, 54 of 180 (30.0%) retained their native liver. Of these, 72% (39 of 54) had evidence of chronic liver disease at transition, of whom 8 were subsequently lost to follow-up, 9 were transplanted, and 22 remained stable with compensated liver disease. Of the 15 of 54 patients (28%) with no evidence of chronic disease in their native liver disease at transition, 3 were subsequently lost to follow-up; none received transplants, although 3 patients developed new-onset liver disease. All patients transitioned to adult care completed secondary school education (N = 180), with 49% having attended college/university and 87% being in employment or education at the last follow-up. Of female patients, 34% had at least one pregnancy (27 children in 21 women), while 22% of males had fathered a child. Conclusion: Long-term outcomes in BA are good, with patients surviving into adult life. Progression of chronic liver disease and associated morbidity is common in those who retained their native livers, suggesting that these patients require monitoring of liver disease throughout adult life, and early recognition of the need for LT.

Evaluation and Management of Liver Transplant Candidates With Prior Nonhepatic Cancer: Guidelines From the ILTS/SETH Consensus Conference.

Liver transplant in patients with prior nonhepatic cancer is a matter of concern, needing further research, development, and consensus guidelines. This International Liver Transplantation Society/Sociedad Española De Trasplante Hepático consensus conference document focuses on the role of liver transplantation in patients with a prior history of nonhepatic cancer. This document addresses (1) the evaluation of transplant candidates with prior cancers based on the assessment of prognosis, the natural history of individual cancers, and the emerging role for circulating DNA and minimal residual disease in these patients; (2) the impact of prior treatments, including immunotherapy for prior malignancies; and (3) the surveillance of posttransplant cancer recurrence. The consensus statement is based on previously published guidelines, as well as a review of the current, relevant, published literature.

Tacrolimus as an Effective and Durable Second-Line Treatment for Chronic Autoimmune Hepatitis: A Multicentric Study.

BACKGROUND: Autoimmune hepatitis (AIH) is a chronic liver disease able to progress to acute liver failure, cirrhosis, and liver cancer. A significant proportion of patients fail to first-line therapy or develop severe toxicity. AIMS: To assess safety and effectiveness of tacrolimus as a second-line therapy in AIH patients. METHODS: Multicentric retrospective study of AIH patients treated with tacrolimus for at least 3 months as a second-line therapy. Effectiveness was defined as complete normalization of transaminases and IgG. RESULTS: A total of 23 AIH patients were included in the final analysis. In 13% of patients tacrolimus was initiated because of toxicity to previous first-line treatments and the rest were switched because of previous non-efficacy. Tacrolimus was effective in 18 patients (78%; 95%CI: 55.20-91.92%). The median time receiving tacrolimus was 16 months (IQR 20). There was a sustained response with a significant improvement in all liver enzymes and IgG on last follow-up. Only one patient discontinued tacrolimus at the third month because of severe neuropathy, and ototoxicity. Responders were significantly older at diagnosis of AIH (41 ± 13 vs. 27 ± 10 years old; p = 0.0496). CONCLUSION: Tacrolimus is effective and well tolerated as a second-line therapy in patients with AIH.

Estimation of visceral fat is useful for the diagnosis of significant fibrosis in patients with non-alcoholic fatty liver disease.

BACKGROUND: Obesity is a risk factor for non-alcoholic fatty liver disease (NAFLD), although obese patients with NAFLD do not always develop significant fibrosis. The distribution of body fat could predict the risk of NAFLD progression. AIM: To investigate the role of bioelectrical impedance-estimated visceral fat (VF) in assessing NAFLD severity. METHODS: In this cross-sectional study, patients with biopsy-proven NAFLD were prospectively included. All patients underwent anthropometric evaluation, blood tests and bioelectrical impedance analysis. RESULTS: Between 2017 and 2020, 119 patients were included [66.4% male, 56 years (SD 10.7), 62.2% obese, 61.3% with metabolic syndrome]. Sixty of them (50.4%) showed significant fibrosis (≥ F2) in liver biopsy. Age, VF and metabolic syndrome were associated with significant fibrosis (61 years vs 52 years, 16.4 vs 13.1, 73.3% vs 49.2%, respectively; P < 0.001 for all). In the multivariate analysis, VF and age were independently associated with significant fibrosis (VF, OR: 1.11, 95%CI: 1.02-1.22, P = 0.02; age, OR: 1.08, 95%CI: 1.03-1.12, P < 0.01). A model including these variables showed and area under the receiver operating characteristic curve (AUROC) of 0.75, which was not inferior to transient elastography or NAFLD fibrosis score AUROCs. We developed a nomogram including age and VF for assessing significant fibrosis in routine practice. CONCLUSION: VF is a surrogate marker of liver fibrosis in patients with NAFLD. Bioelectrical impedance analysis is an inexpensive and simple method that can be combined with age to guide patient referral when other resources may be unavailable.

Identification of novel variants in ten patients with Hermansky-Pudlak syndrome by high-throughput sequencing.

Background: Hermansky-Pudlak syndrome (HPS) is a rare inherited platelet disorder characterized by bleeding diathesis, oculocutaneous albinism (OCA) and a myriad of often-serious clinical complications. Methods: We established the clinical and laboratory phenotype and genotype of six unrelated pedigrees comprising ten patients with clinical suspicion of HPS; including platelet aggregation, flow cytometry, platelet dense granule content, electron microscopy and high-throughput sequencing (HTS). Results: The clinical presentation showed significant heterogeneity and no clear phenotype-genotype correlations. HTS revealed two known and three novel disease-causing variants. The Spanish patients carried a homozygous p.Pro685Leufs17* deletion (n = 2) in HPS4, or the novel p.Arg822* homozygous variant (n = 1) in HPS3. In the case of two Turkish sisters, a novel missense homozygous HPS4 variant (p.Leu91Pro) was found. In two Portuguese families, genetic studies confirmed a previously reported nonsense variant (p.Gln103*) in DTNBP1 in three patients and a novel duplication (p.Leu22Argfs*33) in HPS6 in two unrelated patients. Conclusions: Our findings expand the mutational spectrum of HPS, which may help in investigating phenotype-genotype relationships and assist genetic counselling for affected individuals. This approach is a proof of principle that HTS can be considered and used in the first-line diagnosis of patients with biological and clinical manifestations suggestive of HPS. Key messages We established the relationships between the clinical and laboratory phenotype and genotype of six unrelated pedigrees comprising ten patients with clinical suspicion of HPS. Molecular analysis is useful in confirming the diagnosis and may offer some prognostic information that will aid in optimizing monitoring and surveillance for early detection of end-organ damage. This approach is a proof of principle that HTS can be considered and used in the first-line diagnosis of patients with biological and clinical manifestations suggestive of HPS.

Stretching the boundaries for liver transplant in the 21st century.

Given the high waiting list mortality, there is a clear need to identify strategies to increase the number of livers for transplantation. Some strategies require policy changes, whereas others depend on a better understanding of available opportunities. We divided the strategies to increase the number of livers for transplantation into two categories-those aiming to increase the use of organs considered to be of suboptimal quality, and those aiming to increase the use of organs considered to be of suboptimal size. Enough evidence suggests that, if considered in the context of other donor and recipient variables, grafts from elderly donors are a safe option. The severity of steatosis, and not simply its presence, is an important factor in contemplating the utility of steatotic grafts. Use of organs that have steatosis together with other factors that define extended-criteria organs should be avoided, particularly prolonged cold ischaemia time. Donation after circulatory death has an important role in increasing the donor pool, given the wide availability of organs from donors with this cause of death. This type of donation is hampered by a higher risk of ischaemia-reperfusion injury than other types of donation, which can result in graft complications and potential graft loss. Different types of machine perfusion have the potential to overcome these issues, and further research is needed to establish the best techniques and most cost-effective models. Despite the scarcity of data, the availability of safe and highly effective antiviral therapies means that the use of donors infected with hepatitis C virus (HCV) in recipients who are HCV negative can be considered as a strategy to increase the donor pool. Although data on transplantations using livers from living donors in patients with a Model for End-Stage Liver Disease (MELD) score higher than 20-24 are scarce, outcomes are similar to those achieved in patients with lower MELD scores, at least in reference centres. Increased use of split livers is an option if donors and recipients are carefully selected.

Risk of cirrhosis-related complications in patients with advanced fibrosis following hepatitis C virus eradication.

BACKGROUND & AIMS: The risk of hepatocellular carcinoma (HCC) is reduced but not eradicated among patients with hepatitis C virus (HCV)-induced advanced hepatic fibrosis who attained sustained viral response (SVR). We aimed to assess the risk of cirrhosis-related complications in this specific group of patients. METHODS: Data from previously reported Western cohort studies including patients with chronic HCV infection and bridging fibrosis or cirrhosis who attained SVR were pooled for survival analyses on the individual patient level. The primary endpoint was HCC and the secondary endpoint was clinical disease progression, defined as liver failure, HCC or death. RESULTS: Included were 1000 patients with SVR. Median age was 52.7 (IQR 45.1-59.7) years, 676 (68%) were male and 842 (85%) had cirrhosis. Median follow-up was 5.7 (IQR 2.9-8.0) years. Fifty-one patients developed HCC and 101 had clinical disease progression. The cumulative 8-year HCC incidence was 1.8 (95% CI 0.0-4.3) among patients with bridging fibrosis and 8.7% (95% CI 6.0-11.4) among those with cirrhosis (p=0.058). Within the cirrhosis group, the 8-year HCC incidence was 2.6% (95% CI 0.0-5.5) among patients <45years, 9.7% (95% CI 5.8-13.6) among patients from 45-60years, and 12.2% (95% CI 5.3-19.1) among patients >60years of age at start of therapy (p=0.006). Multivariable Cox analyses indicated that higher age, lower platelet count and diabetes mellitus were independently associated with development of HCC. After 8years 4.2% (95% CI 0.1-8.3) of patients with bridging fibrosis and 15.8% (95% CI 12.3-19.3) of patients with cirrhosis experienced clinical disease progression (p=0.007). CONCLUSIONS: Patients with HCV-induced cirrhosis and SVR showed an annual risk of approximately 1% for HCC and 2% for clinical disease progression. Therefore, to prevent HCC surveillance, chronic HCV infection should preferably be treated before cirrhosis has developed. LAY SUMMARY: Patients with cirrhosis who were able to eradicate their chronic HCV infection remain at substantial risk of primary liver cancer. The risk of liver cancer increases with higher age, laboratory makers suggesting more severe liver disease, and presence of diabetes mellitus. Also after successful antiviral therapy patients with HCV-induced cirrhosis should thus remain included in follow-up for early detection of liver cancer.

Prevalence and outcome of portal thrombosis in a cohort of cirrhotic patients undergoing liver transplantation.

INTRODUCTION: The prevalence of portal vein thrombosis (PVT) in patients that have undergone liver transplantation (LT) is 9.7% (SD 4.5). The aim of our study was to determine the prevalence, assess the factors that are associated with PVT and clarify their association with prognosis in patients with liver cirrhosis (LC) and LT. AIMS AND METHODS: From 2005 to 2014, laboratory, radiological and surgical data were collected from patients with LC in our center who had undergone LT for the first time. RESULTS: One hundred and ninety-one patients were included. The mean age was 55 (SD 9), 75.4% of patients were male and 48.7% had HCV. The Child-Pugh scores were A/B/C 41.9%/35.9%/25.5% and the MELD score was 15 (SD 6). Previous decompensations were: ascites (61.4%), hepatic encephalopathy (34.4%), variceal bleeding (25.4%), hepatocellular carcinoma (48.9%) and spontaneous bacterial peritonitis (SPB) (14.3%). The mean post-transplant follow-up was 42 months (0-113). PVT was diagnosed at LT in 18 patients (9.4%). Six patients were previously diagnosed using imaging tests (33.3%): 2 patients (11.1%) by DU and 4 patients (22.2%) by CT scan. All patients with PVT had DU in a mean time of 6 months before LT (0-44) and 90 patients (47.1%) had a CT scan in a median time of 6 months before LT (0-45). PVT was significantly related to the presence of SBP (33.3% vs 12.6%; p = 0.02) and lower levels of albumin (3.1g/dl vs 3.4g/dl; p = 0.05). MELD was higher in patients with PVT (16.6 vs 14.9; p = 0.3). There were no significant differences with regard to the need for transfusion of blood components. Moreover, the surgery time was similar in both groups. PVT correlated with a higher mortality in the first 30 days (8.8% vs 16.7%; p = 0.2). CONCLUSION: Prior history of SBP and lower levels of albumin were identified as factors associated with PVT. The pre-transplant diagnosis rate is very low and the presence of PVT may have implications for short-term mortality.

Transarterial chemoembolisation in intermediate-stage hepatocellular carcinoma. Survey on clinical practice in hospitals in the Madrid Region.

BACKGROUND: Transarterial chemoembolisation (TACE), having demonstrated survival benefits, is the treatmentof choice in intermediate-stage hepatocellular carcinoma, although there is great heterogeneity in its clinical application. MATERIAL AND METHODS: A survey was sent to the Madrid Regional hospitals to assess applicability, indications and treatment protocols. The assessment was made overall and according to the type of hospital (groups A vs. B and C). RESULTS: Seventeen out of 22 hospitals responded (8/8 group A, 9/ 14 group B-C). All do/indicate transarterial chemoembolisation, 13/17 at their own facilities. Eight of the 17 hospitals have multidisciplinary groups (5/8 A, 3/9 B-C). Nine hospitals perform > 20 procedures/year (7 group A), and 6 from group B-C request/perform < 10/year. It is performed on an "on-demand" basis in 12/17. In 5 hospitals, all the procedures use drug-eluting beads loaded with doxorubicin. The average number of procedures per patient is 2. The mean time from diagnosis of hepatocellular carcinoma to transarterial chemoembolisation is ≤ 2 months in 16 hospitals. In 11/17 hospitals, response is assessed by computed tomography. Radiological response is measured without specific criteria in 12/17 and the other five hospitals (4 group A) assessed using standardised criteria. CONCLUSION: Uniformity among the Madrid Regional hospitals was found in the indication and treatment regimen. The use of DEB-TACE has become the preferred form of TACE in clinical practice. The differentiating factors for the more specialised hospitals are a larger volume of procedures, decision-making by multidisciplinary committees and assessment of radiological response more likely to be standardised.

Diagnóstico posparto de la enfermedad de Wilson en gestante con síndrome HELLP y coagulopatía / Postpartum diagnosis of Wilson disease in a pregnant woman with HELLP syndrome and coagulopathy

El síndrome HELLP es una entidad clínico-analítica definida por anemia hemolítica microangiopática, elevación de enzimas hepáticas y trombocitopenia. La afectación hepática del síndrome es común a diversas hepatopatías. Algunas, inherentes a la gestación (hígado graso agudo del embarazo, colestasis intrahepática gestacional) y otras relativas a enfermedad intercurrente (hepatitis agudas virales) o hepatopatía crónica previa. Se presenta un caso clínico de diagnóstico posparto de hepatopatía crónica por enfermedad de Wilson (EW), que comienza en el tercer trimestre de gestación con síndrome HELLP asociado a insuficiencia hepática y coagulopatía. Se revisan los posibles diagnósticos diferenciales y la literatura científica al respecto. Conclusión. Es importante la realización de un adecuado diagnóstico diferencial del síndrome HELLP, ya que no siempre es secundario a la preeclampsia gestacional, pudiendo ser el punto de partida para el diagnóstico de otras hepatopatías agudas o crónicas subyacentes (AU)

HELLP syndrome is a clinical-analytical entity defined by microangiopathic hemolytic anemia, elevated liver enzymes, and thrombocytopenia. Liver involvement in this syndrome is common to several liver diseases. Some of these liver diseases are inherent to pregnancy (acute fatty liver of pregnancy, gestational intrahepatic cholestasis), while others are related to intercurrent disease (acute viral hepatitis) or to previous chronic liver disease. We report a case of postpartum diagnosis of chronic liver disease secondary to Wilson disease, with onset in the third trimester of pregnancy and HELLP syndrome associated with acute liver failure and coagulopathy. We review the differential diagnosis and the scientific literature on the topic. Conclusion. A correct differential diagnosis of HELLP syndrome is important because this syndrome is not always secondary to gestational preeclampsia and can be the starting point for the diagnosis of other acute or chronic liver diseases (AU)

Efficacy and safety of entecavir and/or tenofovir in hepatitis B compensated and decompensated cirrhotic patients in clinical practice.

This study aimed to evaluate the efficacy and safety of entecavir and/or tenofovir in compensated (CC) or decompensated (DC) hepatitis B cirrhotic patients in real-life clinical practice. Of the 48 patients, included between April 2007 and March 2010, 12 were DC. The mean age was 55 ± 12.2 years, 85.4% were Caucasians and 8 patients were HBeAg positive. Mean viral load was 5.2 ± 1.9 log(10) UI/mL. HBV-DNA undetectability at 3, 6, 12 and 24 months were 53.3%, 78.3%, 83.7% and 97.1%, respectively, similar in CC and DC. At 6 and 12 months, ≥ 80% of CC achieved ALT normalization, while only 42.9% and 71.4% in DC. After a median follow-up of 27.1 (0.7-45.3) months, 43 patients were Child Pugh Turcotte (CPT) class A (n = 39 at entry). In DC, progressive improvement in the MELD scores was observed: 12.73 (SD 4.5), 10.4 (SD 3.6) and 8.2 (SD 2.6), at baseline, 12 and 24 months, respectively. During follow-up, 7 patients died, 4 received liver transplantation and 5 developed hepatocellular carcinoma. In three out of four DC who died due to hepatic causes, these events occurred between the first 0.7 and 6.7 months, and all were CPT class C. Cumulative survival in CC vs. DC at 12 and 24 months were 94.4% vs. 66.7%, and 88.2% vs. 57.1%, respectively (log rank p = 0.03). No severe adverse events associated with entecavir or tenofovir were reported. In conclusion, in compensated and decompensated cirrhotic patients, entecavir and tenofovir were effective and well tolerated.

Dysplasia and colorectal cancer in a patient with ulcerative colitis and primary sclerosing cholangitis: a case report and a short review of the literature.

Primary sclerosing cholangitis is a chronic progressive disorder which involves the medium size and large ducts in the intrahepatic and extrahepatic biliary tree. The great majority of cases have underlying inflammatory bowel disease, mainly ulcerative colitis. A higher risk of colorectal cancer has been described among ulcerative colitis patients with primary sclerosing cholangitis. Here we report a case of a primary sclerosing cholangitis in a young male with a newly diagnosed ulcerative colitis presenting with colonic dysplasia. Surveillance for colorectal cancer should be strongly recommended in this group of patients.

Autoimmune hepatitis after long-term methotrexate therapy for rheumatoid arthritis.

Methotrexate (MTX) therapy may be effective in patients with rheumatoid arthritis (RA) or psoriasis due to its anti-inflammatory and immunosuppressive properties. Potential liver toxicity of MTX exists, but the incidence of MTX-specific lesions in liver biopsy of patients with RA and elevated serum transaminase levels is rare; however, severe hepatic damage may occurs unexpectedly in these patients. We describe the first documented case of an adult patient with RA who developed an acute flare of severe hepatitis after long-term therapy with MTX. Autoantibodies positivity, elevated serum IgG levels and compatible liver biopsy findings prompted us to diagnose autoimmune hepatitis, most probably triggered by a breakdown of immune tolerance induced by MTX. A complete remission was achieved in this patient with corticosteroids therapy.

Evaluación de la fibrosis hepática mediante elastografía transitoria en pacientes tratados con metotrexato / Evaluation of liver fibrosis by transient elastography in methotrexate treated patients

Fundamento y objetivos: La seguridad del metotrexato (MTX) está en entredicho debido al riesgo de inducción de fibrosis hepática (FH). Como la elastografía de transición (FibroScan®) es una técnica no invasiva eficaz para evaluar la FH, nos planteamos como objetivos la valoración de la FH en enfermos tratados con MTX, su relación con la duración del tratamiento y la dosis acumulada, y su dependencia de la enfermedad de base. Pacientes y métodos:Se ha realizado un estudio prospectivo incluyendo pacientes tratados con MTX por artritis reumatoide, enfermedad inflamatoria intestinal y psoriasis. El grado de elasticidad hepática se midió por FibroScan®. Los valores de corte para la FH se establecieron de acuerdo con el índice METAVIR.Resultados: Se incluyeron 53 pacientes (22 varones, edad media de 55 [15] años) con las siguientes enfermedades: artritis reumatoide en 17 (32%), enfermedad inflamatoria intestinal en 18 (34%) y psoriasis en 18 (34%) pacientes. La dosis media acumulada de MTX fue de 1.805 (1.560) mg y el tiempo medio de duración del tratamiento de 178 semanas. El valor medio de la elastografía hepática fue de 6,19 (2,43) KPa. En 49 pacientes (92%) se apreció ausencia o ligera fibrosis (F ≤ 2) y solo 4 (7,5%) pacientes presentaron una fibrosis avanzada (F ≥ 3). No se apreciaron diferencias significativas según la duración del tratamiento o la dosis acumulada de MTX. Conclusiones:El tratamiento con MTX es seguro en lo que respecta a la inducción de FH. El FibroScan® es una técnica eficaz para monitorizar la FH en los pacientes tratados con MTX (AU)

Background and aims: Methotrexate (MTX) safety is questioned by the risk of inducing liver fibrosis (LF). As transient elastography (FibroScan®) is an effective non-invasive technique to evaluate LF, our aims were to assess LF in MTX-treated patients, to evaluate LF regarding treatment duration and cumulative dose, and to determine differences depending on the underlying disease. Patients and methods: Prospective study including patients with rheumatoid arthritis, inflammatory bowel disease, and psoriasis treated with MTX. Hepatic stiffness was determined by FibroScan®. The LF cut-off values were established using METAVIR score. Results: Of 53 patients, 22 were men (41.5%), mean age was 55 (15) years, 17 (32%) had rheumatoid arthritis, 18 (34%) inflammatory bowel disease, and 18 (34%) psoriasis. Mean MTX cumulative dose was 1,805 (1,560) mg, and mean treatment duration was 178 weeks. Mean hepatic stiffness was 6.19 (2.43) KPa. In 49 patients (92.5%), absence/mild LF was found (F ≤ 2), and 4 patients (7.5%) had advanced LF (F ≥ 3). Treatment duration or cumulative doses of MTX were not associated with LF. Conclusions: Regarding LF development, MTX therapy is safe. FibroScan® is useful for monitoring LF in MTX-treated patients (AU)

The molecular and pathophysiological implications of hepatitis B X antigen in chronic hepatitis B virus infection.

Hepatitis B virus is considered one of the most significant environmental carcinogens in humans. Because the mechanisms of HBV replication and the development of hepatocellular carcinoma (HCC) are partially known, HBV-associated pathogenesis remains a challenge to increase its understanding. Evidence suggests that the regulatory protein hepatitis B virus X (HBx) mediates the establishment and maintenance of the chronic carrier state. HBx is a multifunctional and potentially oncogenic protein that is conserved among mammalian hepadnaviruses; it is produced very early after infection and throughout the chronic phase. HBx exerts its effects by interacting with cellular proteins and activating various signaling pathways. HBx stimulates the transcription of genes that regulate cell growth, apoptosis, and DNA repair. It also interacts with proteasome subunits and affects mitochondrial stability. Moreover, HBx participates in processes that are associated with the progression of chronic liver disease, including angiogenesis and fibrosis. This review discusses the function of HBx in the life cycle of HBV and its contribution to the pathogenesis of HCC.