Interleukin-37 suppresses the cytotoxicity of hepatitis B virus peptides-induced CD8+ T cells in patients with acute hepatitis B.

Interleukin-37 (IL-37) is a newly identified anti-inflammatory cytokine, owning immunosuppressive activity in infectious diseases. The aim of this study was to investigate the regulatory function of IL-37 on CD8+ T cells during hepatitis B virus (HBV) infection. Eighteen acute hepatitis B (AHB) patients, thirty-nine chronic hepatitis B (CHB) patients, and twenty controls were enrolled. IL-37 concentration was measured by ELISA. IL-37 receptor subunits expressions on CD8+ T cells were assessed by flow cytometry. Purified CD8+ T cells were stimulated with HBV peptides and recombinant IL-37. Perforin and granzyme B secretion was investigated by ELISPOT. Programmed death-1 (PD-1) and cytotoxic T-lymphocyte associated protein-4 (CTLA-4) mRNA expressions were semi-quantified by real-time PCR. CD8+ T cell cytotoxicity was assessed in direct contact and indirect contact coculture with HepG2.2.15 cells. Plasma IL-37 level was down-regulated and negatively correlated with aminotransferase levels in AHB patients. There were no significant differences of IL-37 receptor subunits among AHB patients, CHB patients, and controls. Exogenous IL-37 stimulation suppressed HBV peptides-induced perforin and granzyme B secretion by CD8+ T cells in AHB patients, but not in CHB patients. Exogenous IL-37 stimulation did not affect proinflammatory cytokines secretion as well as PD-1/CTLA-4 mRNA expressions in CD8+ T cells in AHB and CHB patients. Exogenous IL-37 stimulation dampened HBV peptide-induced CD8+ T cell cytotoxicity in a cell-to-cell contact manner. The current data indicated that acute HBV infection might induce down-regulation of IL-37, which might be associated with enhanced CD8+ T cell cytotoxicity and liver damage.

Indicación de N-acetilcisteína en distintas formas de toxicidad por paracetamol / Indication of n-acetylcysteine in differents forms of paracetamol toxicity

Introducción: la hepatotoxicidad por paracetamol está relacionada con la formación del metabolito N-acetil-parabenzoquinoneimina (NAPQI) y su falta de detoxificación a través del glutatión, cuyas reservas se deplecionan en el contexto de una sobredosis. La administración de N-acetilcisteína (NAC) como sustancia dadora de grupos tioles (-SH) contribuye a la prevención del daño hepático que puede desarrollarse con dosis terapéuticas o tóxicas. Métodos: se comentan 5 casos de exposición a paracetamol en los cuales se administró NAC por alteración de la función hepática. La gravedad de los cuadros varió en función de las dosis y del tiempo de latencia hasta la consulta. Resultados: cuatro pacientes ingirieron una única dosis tóxica y una paciente recibió la dosis diaria máxima de paracetamol de 4000 mg/día durante 5 días. La paciente que consultó dentro de las 4 horas posteriores a la ingesta no presentó elevación de transaminasas. Todas las pacientes recibieron NAC y sus valores de enzimas hepáticas se normalizaron al momento del alta. Conclusión: la administración temprana de NAC puede ser útil para prevenir daño hepático tanto en ingestas de dosis tóxicas, como en casos de utilización de dosis terapéuticas máximas durante varios días. (AU)

Introduction: paracetamol hepatotoxicity is related to the formation of the metabolite N-acetyl-parabenzoquinoneimine (NAPQI) and its lack of detoxification through glutathione, whose reserves are depleted in paracetamol overdose. The administration of N-acetylcysteine (NAC) as a donor of sulfhydryl groups (-SH) can prevent liver damage that could even occur with therapeutic or toxic doses. Methods: 5 cases of exposure to paracetamol are discussed, in which NAC was administered due to impaired liver function. These manifestations presented different severity depending on the drug doses and the time until medical consultation. Results: four patients ingested single toxic doses and one patient received the maximum daily dose of paracetamol of 4000 mg/day for 5 days. The patient who consulted within 4 hours after ingestion did not present elevation of transaminases. All patients received NAC, with normal liver enzymes at discharge. Conclusion: the early administration of NAC may be useful to prevent liver damage both in toxic dose intakes and in cases of use of maximum therapeutic doses for several days. (AU)

The association between N-acetylcysteine treatment and hepatic healing in patients with non-acetaminophen-induced liver injury in pediatric intensive care: A single-center retrospective study.

OBJECTIVE: The aim of this study was to determine the association between the use of intravenous N-acetylcysteine (NAC) and hepatic healing in pediatric intensive care unit (PICU) patients with non-acetaminophen-induced hepatic injury, except for acute liver failure. METHODS: The data of patients who received intravenous NAC as adjuvant therapy for transaminase levels more than sixfold normal values during their PICU stay between 2010 and 2014 were retrospectively collected from the medical records database. The patients who did not receive NAC with elevated transaminase levels during their PICU stay between 2014 and 2018 were also collected as the standard of care (SOC) cohort. RESULTS: More than 50% of the liver injuries were secondary to acute hypoxia, hypotension, sepsis, and inflammation. The median number of elevated transaminase period (ETP) days of the NAC and SOC groups were 5 (IQR: 4) and 4 (IQR: 4), respectively (p = 0.17). There was no significant difference between the groups in terms of minimum and maximum laboratory values during ETP. There was no significant difference in terms of ETP and maximum ALT levels between the NAC and SOC groups in the hypoxia-hypotension subgroup. CONCLUSION: This study did not show an association between indirect measures of hepatic healing and post-insult use of NAC in pediatric liver injury in the PICU setting.

The involvement of TGF-ß1 /FAK/α-SMA pathway in the antifibrotic impact of rice bran oil on thioacetamide-induced liver fibrosis in rats.

The objective of the current study is to investigate the effect of rice bran oil (RBO) on hepatic fibrosis as a characteristic response to persistent liver injuries. Rats were randomly allocated into five groups: the negative control group, thioacetamide (TAA) group (thioacetamide 100 mg/kg thrice weekly for two successive weeks, ip), RBO 0.2 and 0.4 groups (RBO 0.2mL and 0.4 mL/rat/day, po) and standard group (silymarin 100 mg/kg/day, po) for two weeks after TAA injection. Blood and liver tissue samples were collected for biochemical, molecular, and histological analyses. Liver functions, oxidative stress, inflammation, liver fibrosis markers were assessed. The obtained results showed that RBO reduced TAA-induced liver fibrosis and suppressed the extracellular matrix formation. Compared to the positive control group, RBO dramatically reduced total bilirubin, AST, and ALT blood levels. Furthermore, RBO reduced MDA and increased GSH contents in the liver. Simultaneously RBO downregulated the NF-κß signaling pathway, which in turn inhibited the expression of some inflammatory mediators, including Cox-2, IL-1ß, and TNF-α. RBO attenuated liver fibrosis by suppressing the biological effects of TGF-ß1, α-SMA, collagen I, hydroxyproline, CTGF, and focal adhesion kinase (FAK). RBO reduced liver fibrosis by inhibiting hepatic stellate cell activation and modulating the interplay among the TGF-ß1 and FAK signal transduction. The greater dosage of 0.4 mL/kg has a more substantial impact. Hence, this investigation presents RBO as a promising antifibrotic agent in the TAA model through inhibition of TGF-ß1 /FAK/α-SMA.

Influence of miRNA-30a-5p on Pulmonary Fibrosis in Mice with Streptococcus pneumoniae Infection through Regulation of Autophagy by Beclin-1.

The study is aimed at observing the influence of microribonucleic acid- (miRNA-) 30a-50p on the pulmonary fibrosis in mice with Streptococcus pneumoniae infection through the regulation of autophagy by Beclin-1. Specific pathogen-free mice were instilled with Streptococcus pneumoniae through the trachea to establish the pulmonary fibrosis model. Then, they were divided into the miRNA-30a-50p mimics group (mimics group, n = 10) and miRNA-30a-5p inhibitors group (inhibitors group, n = 10), with the control group (n = 10) also set. Pulmonary tissue wet weight/dry weight (W/D) was detected. The content of tumor necrosis factor-α (TNF-α), interleukin- (IL-) 6, and myeloperoxidase (MPO) was determined using enzyme-linked immunosorbent assay (ELISA). Besides, the changes in the pulmonary function index dynamic lung compliance (Cdyn), plateau pressure (Pplat), and peak airway pressure (Ppeak) were monitored, and the gene and protein expression levels were measured via quantitative PCR (qPCR) and Western blotting. The expression level of miRNA-30a-5p was substantially raised in the mimics group (p < 0.05), but extremely low in the inhibitors group (p < 0.05). The mimics group had obviously raised levels of serum aminotransferase (AST), glutamic-pyruvic transaminase (GPT), alkaline phosphatase (ALP), and pulmonary tissue W/D (p < 0.05). Additionally, the expression levels of TNF-α, IL-6, and MPO were notably elevated in the mimics group, while their expression levels showed the opposite conditions in the inhibitors group (p < 0.05). According to the HE staining results, the inhibitors group had arranged orderly cells, while the mimics group exhibited lung injury, pulmonary edema, severe inflammatory response, and alveolar congestion. In the inhibitors group, Cdyn was remarkably elevated, but Pplat and Ppeak declined considerably (p < 0.05). Besides, the inhibitors group exhibited elevated messenger RNA (mRNA) levels of Beclin-1 and LC3, lowered mRNA levels of α-SMA and p62, a raised protein level of Beclin-1, and a markedly decreased protein level of p62 (p < 0.05). Silencing miRNA-30a-5p expression can promote the expression of Beclin-1 to accelerate the occurrence of autophagy, thereby treating pulmonary fibrosis in mice with Streptococcus pneumoniae infection.

Analysis of risk factors for Gleason score upgrading after radical prostatectomy in a Chinese cohort.

BACKGROUND: To study the risk factors of Gleason score upgrading (GSU) after radical prostatectomy (RP) in a Chinese cohort. METHODS: The data of 637 patients who underwent prostate biopsy and RP in our hospital from January 2014 to January 2021 were retrospectively analyzed. The age, body mass index (BMI), prostate-specific antigen (PSA) level, testosterone (TT) level, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), eosinophil-to-lymphocyte ratio (ELR), aspartate aminotransferase/alanine transaminase (AST/ALT) ratio, clinical stage, the biopsy method, and pathological characteristics of specimens after biopsy and RP were collected for all patients. Univariate analysis and multivariate logistic regression analysis were used to analyze the risk factors of GSU after RP. The predictive efficacy was verified with the area under the curve (AUC) of the receiver operating characteristic (ROC) curve. We performed the analysis separately in the overall cohort and in the cohort with Gleason score (GS) = 6. RESULTS: In the overall cohort, 177 patients (27.79%) had GSU, and in the GS = 6 cohort, 68 patients (60.18%) had GSU. Multivariate logistic regression analysis showed that in the overall cohort, clinical stage ≥T2c (OR = 3.201, p < 0.001), the number of positive cores ≥3 (OR = 0.435, p = 0.04), and positive rate of biopsy (OR = 0.990, p = 0.016) can affect whether GS is upgraded, and the AUC of the combination of the three indicators for predicting the occurrence of GSU was 0.627. In the GS = 6 cohort, multivariate logistic regression analysis showed that clinical stage ≥T2c (OR = 4.690, p = 0.001) was a risk factor for GSU, and the AUC predicted to occur GSU is 0.675. CONCLUSION: Clinical stage ≥T2c, the number of positive cores <3, and lower positive rate of biopsy are the risk factors of GSU. This study may provide some references for clinicians to judge the accuracy of biopsy pathological grading and formulate treatment strategies, but the specific effect still needs clinical practice certification.

Astaxanthin Mitigates Thiacloprid-Induced Liver Injury and Immunotoxicity in Male Rats.

Thiacloprid (TCP) is a widely used neonicotinoid insecticide with a probable toxic hazard to animals and human beings. This hazard has intensified the demand for natural compounds to alleviate the expected toxic insults. This study aimed at determining whether astaxanthin (ASX) could mitigate the hepatotoxic effect of TCP and diminish its suppressive effect on immune responses in rats. Animals received TCP by gavage at 62.1 mg/kg (1/10th LD50) with or without ASX at 40 mg/kg for 60 days. Intoxicated rats showed modulation of serum transaminases and protein profiles. The hemagglutination antibody titer to sheep red blood cells (SRBC) and the number of plaque-forming cells in the spleen were reduced. The cell-mediated immunity and phagocytosis were suppressed, while serum interleukins IL-1ß, IL-6, and IL-10 were elevated. Additionally, malondialdehyde, nitric oxide, and 8-hydroxy-2'-deoxyguanosine levels were increased in the liver, spleen, and thymus, with depletion of glutathione and suppression of superoxide dismutase and catalase activities. The expressions of inducible nitric oxide synthase and the high mobility group box protein 1 genes were upregulated with histomorphological alterations in the aforementioned organs. Cotreatment with ASX markedly ameliorated the toxic effects of TCP, and all markers showed a regression trend towards control values. Collectively, our data suggest that the protective effects of ASX on the liver and immune system of TCP-treated animals depend upon improving the antioxidant status and relieving the inflammatory response, and thus it may be used as a promising therapeutic agent to provide superior hepato- and immunoprotection.

Detection of Circulating Tumor DNA Methylation in Diagnosis of Colorectal Cancer.

INTRODUCTION: Emerging evidence has demonstrated the potential of the circulating tumor DNA (ctDNA) methylation in the application of cancer diagnosis. METHODS: Three genes including Septin9, Syndecan-2 (SDC2), and branched-chain amino acid transaminase 1 (BCAT1), which have been well demonstrated to have aberrant expression in colorectal cancer (CRC) as tumor suppressors, were selected for detection. A total of 234 peripheral plasma samples from 104 patients with CRC and 130 patients with colorectal polyps, and 60 plasma samples from healthy controls, were collected before any treatment. A real-time polymerase chain reaction-based gene panel was used to detect the methylation of Septin9, SDC2, and BCAT1. The composite score (P) was calculated according to the cycle threshold values of the 3 methylated genes using the logistic regression equation. RESULTS: The ctDNA methylation of the 3 genes had a significantly higher level in patients with CRC, compared with patients with colorectal polyps and healthy controls. The composite score (P) showed association with tumor stages in CRC but not with the tumor location (colon or rectum). In addition, BCAT1 and Septin9 showed better performance for CRC diagnosis, by which CRC was able to distinguish from polyps with sensitivity of 83.7%, specificity of 93.9%, and area under the curve of 0.908. The diagnostic efficiency was significantly improved by combining composite score (P), carcinoembryonic antigen, and fecal immunochemical test for hemoglobin (area under the curve = 0.962). DISCUSSION: The composite score (P) derived from the ctDNA methylation levels of Septin9, SDC2, and BCAT1 can be used for CRC diagnosis with high sensitivity and high specificity. A combination of ctDNA methylation, carcinoembryonic antigen, and fecal immunochemical test for hemoglobin was proved to be the most effective approach to diagnose CRC.

Congenital hepatic fibrosis: case report and review of literature.

Congenital hepatic fibrosis (CHF) is a rare autosomal recessive disease derived from biliary dysgenesis secondary to ductal plate malformation; it often coexists with Caroli's disease, von Meyenburg complexes, autosomal dominant polycystic kidney disease (ADPKD), and autosomal recessive polycystic kidney disease (ARPKD). Although CHF was first named and described in detail by Kerr et al. in 1961. Its pathogenesis still remains unclear. The exact incidence and prevalence are not known, and only a few hundred patients with CHF have been reported in the literature to date. However, with the development of noninvasive diagnostic techniques such as ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI), CHF may now be more frequently detected. Anatomopathological examination of liver biopsy is the gold standard in diagnosis of CHF. Patients with CHF exhibit variable clinical presentations, ranging from no symptoms to severe symptoms such as acute hepatic decompensation and even cirrhosis. The most common presentations in these patients are splenomegaly, esophageal varices, and gastrointestinal bleeding due to portal hypertension. In addition, in younger children, CHF often is accompanied by renal cysts or increased renal echogenicity. Great variability exists among the signs and symptoms of the disease from early childhood to the 5th or 6th decade of life, and in most patients the disorder is diagnosed during adolescence or young adulthood. Here, we present two cases of congenital hepatic fibrosis in 2-years-old girl and 12-year-old male who had been referred for evaluation of an abdominal distension with persistent hyper-transaminasemia and cholestasis, the diagnostic was made according to the results of medical imaging (CT or MRI), a liver biopsy, and genetic testing.

The protective role of protocatechuic acid against chemically induced liver fibrosis in vitro and in vivo.

Liver fibrosis is the result of long-term liver injury and has a high incidence worldwide. Protocatechuic acid (PCA) is ubiquitous in vegetables, nuts, brown rice and herbal medicines, which is reported to possess anti-asthmatic, anti-cancer, and anti-oxidation properties. Our research aimed to investigate the effect of PCA on liver fibrosis. In vitro, TNF-α-induced hepatic stellate cell (HSC) model was used to assess the anti-fibrosis effects of PCA. In vivo, mice were treated with thioacetamide (TAA) to develop liver fibrosis. Body weight, organ index, histological changes, and proteins alteration of factors associated with TGF-ß signaling pathway were used to assess the anti-fibrosis effects of PCA. Our results showed that PCA not only inhibited cell viability in TNF-α activated HSC-T6 cells in vitro, but also efficiently mitigated TAA-induced liver damage and fibrosis in vivo. Further experiments indicated that PCA played a protective role in liver fibrosis through regulation of the TGF-ß signaling pathway downregulating the protein expression of p-Smad2, p-ERK, c-Jun. In summary, our findings provide a pharmacological justification for the clinical application of PCA in preventing or treating liver fibrosis.

Comparison of clinical features between immune-related sclerosing cholangitis and hepatitis.

Background Immune-related hepatotoxicity is often regarded as immune-related hepatitis (irHepatitis) despite including immune-related sclerosing cholangitis (irSC). This study examined the clinical differences between irSC and irHepatitis. Methods A single-center retrospective study of 530 consecutive patients who received immunotherapy between August 2014 and April 2020 was performed. IrSC and irHepatitis were respectively defined as the radiological presence and absence of bile duct dilation and wall thickness. Results Forty-one patients (7.7%) developed immune-related hepatotoxicity. A CT scan was performed on 12 patients, including 11 of 12 with ≥ grade 3 aminotransferase elevations. IrSC and irHepatitis were diagnosed in 4 (0.8%) and 8 (1.5%) patients, respectively. All the irSC patients had been treated with anti-PD-1. IrHepatitis was more common among patients receiving anti-CTLA-4 than among those receiving anti-PD-1/PD-L1 inhibitors (14%, 7/50 vs. 0.2%, 1/480, P < 0.001). A ≥ grade 2 alkaline phosphatase (ALP) elevation resulting in a cholestatic pattern was seen in all 4 irSC patients. Among the irSC patients, 3 (3/4, 75%) developed ≥ grade 3 aminotransferases elevation. The median duration from the start of immunotherapy until ≥ grade 2 liver enzymes elevation was 257 and 55.5 days in irSC and irHepatitis patients. The median times for progression from grade 2 to 3 liver enzyme elevation were 17.5 and 0 days, respectively. Conclusions IrSC and irHepatitis have different characteristics in the class of immune checkpoint inhibitor and onset pattern. Radiological examination for the diagnosis of irSC should be considered for patients with ≥ grade 2 ALP elevation resulting in a cholestatic pattern. (Registration number J2020-36, Date of registration June 3, 2020).

Eribulin, Child-Pugh score, and liver-function tests: lessons from pivotal breast cancer studies 301 and 305.

BACKGROUND: The recommended starting dose of eribulin in patients with hepatic impairment is based on the Child-Pugh score, largely informed by a pharmacokinetic study of 18 patients. In the pivotal studies of eribulin in metastatic breast cancer (Study 301 and Study 305 [EMBRACE]), entry criteria and dose modifications were based on liver-function test (LFT) results rather than Child-Pugh score. In populations such as patients with metastatic breast cancer, in which metastatic infiltration is the predominant cause of hepatic impairment, using Child-Pugh score may be problematic; in clinical practice, it has been more common for oncologists to make dosing decisions based on LFTs. To address this, the effects of abnormal baseline LFT results on eribulin efficacy and safety were investigated. METHODS: In this pooled post hoc analysis, 1062 patients who were randomized to receive eribulin in Studies 301 and 305 were divided into 4 groups: (A) no elevated LFT results (no liver impairment); (B) increased levels of aspartate aminotransferase and/or alanine aminotransferase; (C) decreased albumin and/or increased levels of aspartate aminotransferase and/or alanine aminotransferase but not increased bilirubin; and (D) increased bilirubin. Patients were subcategorized by presence of liver metastasis. Drug exposure, dose intensity, and treatment-emergent adverse events (TEAEs) were analyzed. RESULTS: Eribulin mesylate mean dosage was 0.82 (group A)-0.65 mg/m2/week (group D). Group D had shorter treatment, more dose reductions/delays, more TEAEs leading to dose modifications, and numerically lower objective response rates and clinical benefit rates versus groups A-C. TEAE rates leading to dose modification were similar between group D (45.5%) and groups A-C (range, 43.5-54.9%) in the absence of liver metastases, but higher in group D (91.3%) compared with groups A-C (range, 41.7-54.3%) if liver metastases were present. CONCLUSIONS: Mild elevations in bilirubin levels were associated with increased toxicity and a greater requirement for dose modifications. Based both on these study data and existing recommendations, we propose a novel scheme to guide initial dose selection in patients with metastatic breast cancer and hepatic impairment that is based on LFTs rather than Child-Pugh score.

Tectona grandis leaf extract ameliorates hepatic fibrosis: Modulation of TGF- ß /Smad signaling pathway and upregulating MMP3/TIMP1 ratio.

ETHNOBOTANICAL RELEVANCE: Tectona grandis L.f (or syn: Jatus grandis (L.f.) Kuntze Revis), from family Lamiaceae, also known as Teak, is widely recognized in ayurvedic system of medicine and confer curative potential against inflammation, liver disorders, biliousness, diabetes, bronchitis, leprosy and dysentery. Its leaves are rich source of edible food colorant and reported nontoxic for liver and various organs. AIM OF STUDY: Hepatic injury progression to liver cirrhosis and cancer is a serious health issue across the world. Currently, anti-fibrotic therapeutic options are limited and expensive with no FDA approved direct anti-hepato-fibrotic drug validated in clinic. Thus, the aim of this study was to understand ameliorative effect of Tectona grandis L.f, leaves in early liver fibrosis. METHOD AND RESULTS: C57BL/6 mice suffering from CCl4 induced liver injury, were orally administered at three different doses (50, 100 & 200 mg/kg) of Tectona grandis L.f, leaf extract, thrice a week, up to 4 and 8 weeks. Anti-fibrotic effect was evaluated through animal body/liver weight measurements, serological tests (AST, ALT, GSH, MDA and LDH assays), tissue hydroxyproline content, and histochemical analysis (H&E, Masson trichrome, Sirius red and αSMA localization). Moreover, transcriptional and post-transcriptional expression of fibrosis associated biomarkers and TGF-ß/Smad cascade were analyzed. It was observed that 100 mg/kg dose optimally downregulated TGF-ß1/Smad2 with upregulation of Smad7 and regulated αSMA, Col 1, PDGF, TIMP1 and MMP3 expression, post 8 weeks of treatment. In addition, MMP3/TIMP1 ratio was upregulated to 0.7, 2.5 and 1.7 fold at 50 mg/kg, 100 mg/kg & 200 mg/kg treatments respectively, in comparison to untreated liver fibrosis models. The extract contains gallic acid, caffeic acid, sinapinic acid and myricetin when analyzed through high performance liquid chromatography. CONCLUSION: Tectona grandis L.f, leaves have potential to ameliorate liver fibrosis induced by CCl4 in mice via modulation of TGF-ß1/Smad pathway and upregulated MMP3/TIMP1 ratio.

Shwachman-diamond syndrome: A case report.

RATIONALE: The aim of this study was to analyze the genetic abnormalities and clinical manifestations of Shwachman-Diamond syndrome (SDS). PATIENT CONCERNS: A Chinese infant with elevated transaminase and a novel mutation at of sbdsc.258 +2T>C and c.184a>Tc.292G>A. DIAGNOSES: The female patient was 5 months' old at onset, with elevated transaminase as the first manifestation accompanied by restricted growth and development and oily stool. After sequencing the blood samples from patients and their parents, the heterozygous mutations of sbdsc.258 +2T>C and c.184a>T were detected. INTERVENTIONS: After admission, the patient was provided compound glycyrrhizin, Newtide formula milk supplemented with probiotics, fat-soluble vitamins, oral medication to adjust the spleen and stomach, and other symptomatic treatments. OUTCOMES: The stool traits improved, and the levels of liver function transaminases decreased compared with before. LESSONS: SDS is a rare disease with a variety of clinical manifestations. Pancreatic exocrine dysfunction, blood system manifestations, and bone abnormalities are common clinical manifestations, and genetic testing is helpful for diagnosis.

Variables Associated with Detection of Methylated BCAT1 or IKZF1 in Blood from Patients Without Colonoscopically Evident Colorectal Cancer.

BACKGROUND: DNA methylated in BCAT1 and IKZF1 are promising circulating tumor DNA (ctDNA) biomarkers for colorectal cancer detection. This study tested for variables that might be associated with their detection in patients without colonoscopically evident colorectal cancer so-called false positives. METHODS: A retrospective review of demographic and clinical variables was conducted on patients who were assayed for these biomarkers prior to a colonoscopy for any indication. Potential relationships between detection of these biomarkers and patient variables in patients without colorectal cancer were identified by logistic regression. An age- and sex-matched case-control study was undertaken to identify additional associations. RESULTS: A total of 196 of 1,593 patients undergoing colonoscopy were positive for BCAT1 and/or IKZF1 methylation; 70 (35.7%) had confirmed diagnosis of colorectal cancer. Of the 126 false positives, biomarker levels were significantly lower than in those with colorectal cancer (P < 0.05), with the total cell-free circulating DNA concentration associated with biomarker detection (OR, 1.16; 95% CI, 1.10-1.22), and 83 (65.9%) of the non-colorectal cancer cases positive for methylated BCAT1 only. Age ≥70 years was the only demographic variable associated with biomarker detection (OR, 4.31; 95% CI, 1.50-12.41). No significant associations were seen with medications or comorbidities (P > 0.05). Four cases without colonoscopically evident colorectal cancer but with biomarker levels above the median for patients with colorectal cancer were diagnosed with metastatic adenocarcinoma within 1 year. CONCLUSIONS: False-positive results were most commonly associated with detection of methylated BCAT1 only, as well as age ≥70 years. IMPACT: In the absence of colonoscopically evident colorectal cancer, a high level of circulating methylated DNA warrants investigations for cancers at other sites.

Overlap of concurrent extrahepatic autoimmune diseases is associated with milder disease severity of newly diagnosed autoimmune hepatitis.

BACKGROUND: Concurrent extrahepatic autoimmune disorders (CEHAID) are frequently observed in autoimmune hepatitis (AIH). It is not clear whether there is any prognostic significance of CEHAID on AIH. The aim of this study was to examine the prognostic impact of CEHAID and the correlation with the disease severity of AIH. METHODS: This study included 65 hospitalized subjects who fulfilled the accepted criteria for AIH during an 8-year period (2009-2016). All records were manually screened for presence of associated autoimmune diseases. Disease severity of AIH was assessed by liver laboratory tests including the ratio of aspartate aminotransferase to alanine aminotransferase (AST/ALT) and liver histology. RESULTS: Among the enrolled patients, 52 (80%) were female (median age 61 years, IQR 45-75). Fifty-six (86.2%) were classified as type-1 AIH. In 26 (40%) patients at least one additional extrahepatic autoimmune disease was diagnosed. Thirty-four subjects were referred to our hospital because of acute presentation of AIH (supposed by an acute elevation of hepatic enzymes) for subsequent liver biopsy resulting in initial diagnosis of AIH. This group was stratified into 3 subgroups: (A) AIH alone (n = 14); (B) overlap with primary biliary cirrhosis (PBC) / primary sclerosing cholangitis (PSC) (n = 11); and (C) with CEHAID (n = 9). AST/ALT ratio was the lowest in subgroup C (median 0.64, IQR 0.51-0.94; P = 0.023), compared to subgroup A (median 0.91, IQR 0.66-1.10) and subgroup B (median 1.10, IQR 0.89-1.36). Patients with AIH alone showed a trend to the highest grade of fibrosis (mean 2.3; 95% CI: 1.5-3.0) with no statistical significance compared to subjects with CEHAID (lowest grade of fibrosis; mean 1.5; 95% CI: 0.2-2.8; P = 0.380) whereas the ongoing inflammation was comparable. CONCLUSIONS: AST/ALT ratio and extent of fibrosis were lower in subjects with AIH and CEHAID, compared to subjects with only AIH. Therefore, the occurrence of CEHAID might be a predictor for lower disease severity of newly diagnosed acute onset AIH, possibly caused by an earlier diagnosis or different modes of damage.

Hepatopatías autoinmunes. Hallazgos clínicos y de laboratorio en pacientes de un hospital de referencia nacional / Autoimmune liver diseases. Clinical and laboratory findings in patients in a national reference hospital

Introducción. Las enfermedades autoinmunes del hígado son un grupo de patologías caracterizadas por una respuesta autoinmune contra los hepatocitos y/o el epitelio biliar. Sus manifestaciones clínicas son variadas, con alteraciones en las pruebas de función hepática y presencia de autoanticuerpos. Metodología. Estudio observacional descriptivo con 101 pacientes atendidos en el Hospital Universitario de La Samaritana de Bogotá D.C., entre enero a diciembre de 2019, con los diagnósticos de hepatitis autoinmune, colangitis biliar primaria, colangitis esclerosante primaria y síndrome de sobreposición. Se evaluaron los parámetros clínicos y de laboratorio, con el fin de caracterizar su frecuencia en estas patologías, debido a la importancia de un diagnóstico precoz. Resultados. Se encontraron 54 casos de hepatitis autoinmune, 19 casos de colangitis biliar primaria, 4 casos de colangitis esclerosante primaria y 24 casos de síndrome de sobreposición. El 81% fueron mujeres y la edad promedio fue de 55 años. El 39% de los pacientes tenían cirrosis. En general, los resultados se ajustaron a lo descrito internacionalmente, como es el predominio en mujeres y la comorbilidad autoinmune. Conclusión. Los hallazgos indican que cualquier alteración del perfil bioquímico hepático debe ser considerado, y se debe descartar la presencia de hepatopatías autoinmunes para diagnosticarlas de manera precoz, evitando que lleguen a cirrosis y sus complicaciones, con la necesidad de un trasplante hepático como única alternativa terapéutica.

Introduction. Autoimmune liver diseases are a group of pathologies characterized by an autoimmune response against hepatocytes and/or the biliary epithelium. Their clinical manifestations are varied, with alterations in liver function tests and the presence of autoantibodies. Methodology. Descriptive study with 101 patients who attended at the Hospital Universitario de La Samaritana in Bogota D.C., between January and December 2019, with the diagnoses of autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis and overlap syndrome. Clinical and laboratory parameters were evaluated in order to characterize their frequency in these pathologies, due to the importance of an early diagnosis. Results. There were 54 cases of autoimmune hepatitis, 19 cases of primary biliary cholangitis, 4 cases of primary sclerosing cholangitis, and 24 cases of overlap syndrome. Of all patients, 81% were women, the average age was 55 years, and 39% had cirrhosis. In general, the findings were consistent with what has been described worldwide, such as a higher prevalence in women and autoimmune comorbidity. Conclusion. The findings indicate that any alteration in the liver biochemical profile should be considered to rule out an autoimmune liver disease for an early diagnosis, avoiding the possibility of cirrhosis and its complications, with the need for a liver transplant as the only therapeutic alternative.

Uso de corticosteroides no tratamento da lesão hepática aguda grave decorrente de anabolizante estanazolol / Use of corticosteroids in the treatment of stanazolol-induce severe acute liver injury

A busca pelo corpo perfeito pode gerar graves consequências para a população que faz uso indiscriminado de substâncias visando a resultados rápidos. O caso relatado se refere a um pa- ciente de 21 anos, do sexo masculino, na cidade de São Paulo (SP), que apresentou quadro de síndrome colestática 15 dias após uso do anabolizante estanazolol para fins estéticos na ativi- dade física, evoluindo com hepatite medicamentosa grave, com aumento de transaminases, hiperrubilinemia às custas de bilirrubina direta e fatores de coagulação, sem resposta satis- fatória ao tratamento de suporte convencional, com melhora significativa após introdução de corticoterapia.

Searching for the perfect body image can cause severe conse- quences to the population using substances indiscriminately to reach results fast. The case reported refers to a male patient, 21 years old, from the city of São Paulo (SP), who developed choles- tatic syndrome 15 days after the use of the steroid Stanazol for aesthetic purposes during physical activity, progressing with se- vere drug-induced hepatitis, transaminases, bilirubin, and coagu- lation factors increase with no satisfactory response to the con- ventional support treatment, and significant improvement after the introduction of corticotherapy.

Safety and efficacy of cyclin-dependent kinase inhibitor rechallenge following ribociclib-induced limiting hypertransaminasemia.

Cyclin-dependent kinase inhibitors (CDKIs) and endocrine therapy (ET) are the corner-stone of systemic therapy for patients with hormone-positive (HR+) HER2-negative metastatic breast cancer (MBC). However, limited data exist regarding rechallenge treatment strategies with CDKIs after limiting toxicity. In this report, we provide evidence of the safety and efficacy of sequential treatment with palbociclib or abemaciclib in 6 HR+/HER- MBC patients who experienced grade ≥3 ribociclib-induced hypertransaminasemia. Until results from large observational or randomized studies are communicated, empirical evidence may help make individualized decisions on CDKI rechallenge beyond ribociclib-induced unacceptable liver toxicity.

Ghrelin reverses ductular reaction and hepatic fibrosis in a rodent model of cholestasis.

The orexigenic peptide ghrelin (Ghr) stimulates hunger signals in the hypothalamus via growth hormone secretagogue receptor (GHS-R1a). Gastric Ghr is synthetized as a preprohormone which is proteolytically cleaved, and acylated by a membrane-bound acyl transferase (MBOAT). Circulating Ghr is reduced in cholestatic injuries, however Ghr's role in cholestasis is poorly understood. We investigated Ghr's effects on biliary hyperplasia and hepatic fibrosis in Mdr2-knockout (Mdr2KO) mice, a recognized model of cholestasis. Serum, stomach and liver were collected from Mdr2KO and FVBN control mice treated with Ghr, des-octanoyl-ghrelin (DG) or vehicle. Mdr2KO mice had lower expression of Ghr and MBOAT in the stomach, and lower levels of circulating Ghr compared to WT-controls. Treatment of Mdr2KO mice with Ghr improved plasma transaminases, reduced biliary and fibrosis markers. In the liver, GHS-R1a mRNA was expressed predominantly in cholangiocytes. Ghr but not DG, decreased cell proliferation via AMPK activation in cholangiocytes in vitro. AMPK inhibitors prevented Ghr-induced FOXO1 nuclear translocation and negative regulation of cell proliferation. Ghr treatment reduced ductular reaction and hepatic fibrosis in Mdr2KO mice, regulating cholangiocyte proliferation via GHS-R1a, a G-protein coupled receptor which causes increased intracellular Ca2+ and activation of AMPK and FOXO1, maintaining a low rate of cholangiocyte proliferation.