NLRP12 Senses the SARS-CoV-2 Membrane Protein and Promotes an Inflammatory Response.

COVID-19 is an acute respiratory disorder that is caused by SARS-CoV-2, in which excessive systemic inflammation is associated with adverse patient clinical outcomes. Here, we observed elevated expression levels of NLRP12 (nucleotide-binding leucine-rich repeat-containing receptor 12) in human peripheral monocytes and lung tissue during infection with SARS-CoV-2. Co-immunoprecipitation analysis revealed that NLRP12 directly interacted with the M protein through its leucine-rich repeat domain. Moreover, in vitro studies demonstrated that NLRP12 interacted with TRAF3 and promoted its ubiquitination and degradation, which counteracted the inhibitory effect of TRAF3 on the NF-κB/MAPK signaling pathway and promoted the production of inflammatory cytokines. Furthermore, an in vivo study revealed that NLRP12 knockout mice displayed attenuated tissue injury and ameliorated inflammatory responses in the lungs when infected with a SARS-CoV-2 M protein-reconstituted pseudovirus and mouse coronavirus. Taken together, these findings suggest that NLRP12 mediates the inflammatory responses during coronavirus infection.

Prediction of biochemical nonresolution in patients with chronic drug-induced liver injury: A large multicenter study.

BACKGROUND AND AIMS: To clarify high-risk factors and develop a nomogram model to predict biochemical resolution or biochemical nonresolution (BNR) in patients with chronic DILI. APPROACH AND RESULTS: Retrospectively, 3655 of 5326 patients with chronic DILI were enrolled from nine participating hospitals, of whom 2866 underwent liver biopsy. All of these patients were followed up for over 1 year and their clinical characteristics were retrieved from electronic medical records. The endpoint was BNR, defined as alanine aminotransferase or aspartate aminotransferase >1.5× upper limit of normal or alkaline phosphatase >1.1× ULN, at 12 months from chronic DILI diagnosis. The noninvasive high-risk factors for BNR identified by multivariable logistic regression were used to establish a nomogram, which was validated in an independent external cohort. Finally, 19.3% (707 of 3655) patients presented with BNR. Histologically, with the increase in liver inflammation grades and fibrosis stages, the proportion of BNR significantly increased. The risk of BNR was increased by 21.3-fold in patients with significant inflammation compared to none or mild inflammation (p < 0.001). Biochemically, aspartate aminotransferase and total bilirubin, platelets, prothrombin time, sex, and age were associated with BNR and incorporated to construct a nomogram model (BNR-6) with a concordance index of 0.824 (95% CI, 0.798-0.849), which was highly consistent with liver histology. These results were successfully validated both in the internal cohort and external cohort. CONCLUSIONS: Significant liver inflammation is a robust predictor associated with biochemical nonresolution. The established BNR-6 model provides an easy-to-use approach to assess the outcome of chronic DILI.

Hepatic Histopathology Among Excessive Drinkers Without Advanced Liver Disease.

AIMS: Alcohol-associated liver disease represents a spectrum of histopathological changes from steatosis to advanced fibrosis and cirrhosis. The major goals of this retrospective study were to characterize the histologic features in patients with excessive alcohol use who presented with an abnormal hepatic panel and/or abnormal radiographic imaging and did not meet the clinical diagnosis of alcoholic hepatitis or cirrhosis. METHODS: We performed a retrospective study to describe hepatic histology of 62 and 83 excessive drinkers with normal and abnormal serum aspartate transaminase, respectively. The types of inflammatory cells in the liver were characterized by immunohistochemistry for CD4, CD8, CD20, CD68 and myeloperoxidase. RESULTS: Among 62 patients with aspartate aminotransferase (AST) ≤ 50 U/L, 37% had histological evidence of steatosis. Of these, we found evidence of hepatocyte ballooning (21%), lobular inflammation (50%), portal inflammation (52%) and fibrosis (14%). For those with AST > 50 U/L, the presence of hepatic steatosis, lobular inflammation and portal inflammation was observed in 29, 60 and 69% of patients, respectively. Fibrosis was found in 33%, four with bridging fibrosis, and one with cirrhosis. We observed the aggregation of CD68+ macrophages, rather than normally distributed with minimal neutrophilic infiltration. Lobular and portal lymphocytic infiltrations are primarily CD8+ T cells. CONCLUSION: Abnormal hepatic histopathology occurs in excessive drinkers with normal transaminase activity. Future studies to determine the diagnostic modalities to detect such abnormalities and to better understand its clinical implications and long-term outcome are needed.

Emperipolesis mediated by CD8+ T cells correlates with biliary epithelia cell injury in primary biliary cholangitis.

Primary biliary cholangitis (PBC) is an autoimmune disease characterized by chronic destruction of the bile ducts. A major unanswered question regarding the pathogenesis of PBC is the precise mechanisms of small bile duct injury. Emperipolesis is one of cell-in-cell structures that is a potential histological hallmark associated with chronic hepatitis B. This study aimed to clarify the pathogenesis and characteristics of emperipolesis in PBC liver injury. Sixty-six PBC patients, diagnosed by liver biopsy combined with laboratory test, were divided into early-stage PBC (stages I and II, n = 39) and late-stage PBC (stages III and IV, n = 27). Emperipolesis was measured in liver sections stained with haematoxylin-eosin. The expressions of CK19, CD3, CD4, CD8, CD20, Ki67 and apoptosis of BECs were evaluated by immunohistochemistry or immunofluorescence double labelling. Emperipolesis was observed in 62.1% of patients with PBC, and BECs were predominantly host cells. The number of infiltrating CD3+ and CD8+ T cells correlated with the advancement of emperipolesis (R2  = 0.318, P < .001; R2  = 0.060, P < .05). The cell numbers of TUNEL-positive BECs and double staining for CK19 and Ki67 showed a significant positive correlation with emperipolesis degree (R2  = 0.236, P < .001; R2  = 0.267, P < .001). We conclude that emperipolesis mediated by CD8+ T cells appears to be relevant to apoptosis of BEC and thus may aggravate the further injury of interlobular bile ducts.

COVID-19: Abnormal liver function tests.

BACKGROUND & AIMS: Recent data on the coronavirus disease 2019 (COVID-19) outbreak caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has begun to shine light on the impact of the disease on the liver. But no studies to date have systematically described liver test abnormalities in patients with COVID-19. We evaluated the clinical characteristics of COVID-19 in patients with abnormal liver test results. METHODS: Clinical records and laboratory results were obtained from 417 patients with laboratory-confirmed COVID-19 who were admitted to the only referral hospital in Shenzhen, China from January 11 to February 21, 2020 and followed up to March 7, 2020. Information on clinical features of patients with abnormal liver tests were collected for analysis. RESULTS: Of 417 patients with COVID-19, 318 (76.3%) had abnormal liver test results and 90 (21.5%) had liver injury during hospitalization. The presence of abnormal liver tests became more pronounced during hospitalization within 2 weeks, with 49 (23.4%), 31 (14.8%), 24 (11.5%) and 51 (24.4%) patients having alanine aminotransferase, aspartate aminotransferase, total bilirubin and gamma-glutamyl transferase levels elevated to more than 3× the upper limit of normal, respectively. Patients with abnormal liver tests of hepatocellular type or mixed type at admission had higher odds of progressing to severe disease (odds ratios [ORs] 2.73; 95% CI 1.19-6.3, and 4.44, 95% CI 1.93-10.23, respectively). The use of lopinavir/ritonavir was also found to lead to increased odds of liver injury (OR from 4.44 to 5.03, both p <0.01). CONCLUSION: Patients with abnormal liver tests were at higher risk of progressing to severe disease. The detrimental effects on liver injury mainly related to certain medications used during hospitalization, which should be monitored and evaluated frequently. LAY SUMMARY: Data on liver tests in patients with COVID-19 are scarce. We observed a high prevalence of liver test abnormalities and liver injury in 417 patients with COVID-19 admitted to our referral center, and the prevalence increased substantially during hospitalization. The presence of abnormal liver tests and liver injury were associated with the progression to severe pneumonia. The detrimental effects on liver injury were related to certain medications used during hospitalization, which warrants frequent monitoring and evaluation for these patients.

Longitudinal changes of liver function and hepatitis B reactivation in COVID-19 patients with pre-existing chronic hepatitis B virus infection.

AIM: With the current coronavirus disease (COVID-19) pandemic and high endemic levels of chronic hepatitis B virus (HBV) infection worldwide, it is urgent to investigate liver function changes of COVID-19 patients with chronic HBV infection, and how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in turn affects the course of chronic HBV infection. METHOD: We undertook a retrospective study based on 347 COVID-19 patients (21 vs. 326 with vs. without chronic HBV infection). With the propensity score matching (PSM) method, we yielded 20 and 51 matched patients for the HBV group and the non-HBV group, respectively. RESULTS: At the end of follow-up, all of these 71 patients achieved SARS-CoV-2 clearance (P = 0.1). During the follow-up, 30% versus 31.4% in the HBV group versus non-HBV group progressed to severe COVID-19 (P = 0.97). After PSM, the longitudinal changes of median values for liver biochemistries were not significantly different between the two groups. In the HBV group versus non-HBV group, 35% (7/20) versus 37.25% (19/51) (P = 0.86) had abnormal alanine aminotransferase at least once during hospitalization, 30% (6/20) versus 31.37% (16/51) had abnormal aspartate aminotransferase (P = 0.91), 40% (8/20) versus 37.25% (19/51) had abnormal γ-glutamyltransferase (P = 0.83), and 45% (9/20) versus 39.22% (20/51) had abnormal total bilirubin levels (P = 0.91). Moreover, three patients in the HBV group had hepatitis B reactivation. CONCLUSIONS: Liver dysfunction presented in COVID-19 patients with/without chronic HBV. Moreover, those COVID-19 patients co-infected with chronic HBV could have a risk of hepatitis B reactivation. It is necessary to monitor liver function of COVID-19 patients, as well as HBV-DNA levels for those co-infected with HBV during the whole disease course.

[Value of serum osteoprotegerin in noninvasive diagnosis of nonalcoholic steatohepatitis].

OBJECTIVE: To investigate the correlation of serum osteoprotegerin (OPG) with the progression of nonalcoholic fatty liver disease (NAFLD) and the noninvasive prediction and diagnosis of nonalcoholic steatohepatitis (NASH). METHODS: A total of 136 patients with NAFLD were enrolled, and their tissue samples for liver biopsy and serum samples obtained at 1 week after liver biopsy were collected; 83 healthy subjects without the symptoms of fatty liver disease proved by ultrasound examination were enrolled as controls. The physiological indicators including height, body weight, and waist circumference were measured, and body mass index was calculated. The biochemical parameters including alanine aminotransferase (ALT), aspartate aminotransferase (AST), AST/ALT, alkaline phosphatase, gamma-glutamyl transferase, total cholesterol, triglyceride (TG), high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol were measured. Double-antibody sandwich enzyme-linked immunosorbent assay was used to determine the serum level of OPG. The rank sum test, chi-square test, t-test, one-way analysis of variance, Spearman correlation analysis, least significant difference test, and receiver operating characteristic (ROC) curve were applied for statistical analysis of various data. RESULTS: Serum OPG level was correlated with AST and TG (P < 0.05), and was highly correlated with hepatocyte fatty degeneration, ballooning degeneration, intralobular inflammation, portal inflammation, and fibrosis degree (P < 0.01). With the increasing NAFLD activity score (NAS), serum OPG level decreased, and there was a highly negative correlation between them (r = -0.928, P < 0.01). Serum OPG level was significantly lower in NASH patients than non-NASH patients. The area under the ROC curve of serum OPG level was 0.963, and according to the Youden index, its optimal sensitivity and specificity were 96.1% and 97.4%, respectively, at an optimal cut-off value of 242.96 ng/L, which suggested a high diagnostic power. CONCLUSION: In NASH patients, serum OPG level decreases significantly. Serum OPG level can be used as an independent predictive factor to evaluate NASH and its severity, as well as a noninvasive diagnostic index for NASH.

Gynostemma Pentaphyllum ameliorates CCl4-induced liver injury via PDK1/Bcl-2 pathway with comprehensive analysis of network pharmacology and transcriptomics.

BACKGROUND: Gynostemma pentaphyllum (Thunb.) Makino, commonly known as "southern ginseng", contains high amounts of ginsenoside derivatives and exhibits similar biological activities with Panax ginseng (C. A. MEY) (ginseng), which is usually used as a low-cost alternative to ginseng. G. pentaphyllum has therapeutic effects on liver diseases. However, the mechanisms underlying its hepatoprotective action have not been fully elucidated. METHODS: The protective effects of the ethanolic extract of G. pentaphyllum (GPE) were evaluated using an experimental carbon tetrachloride (CCl4)-induced liver disease model. Potential targets of GPE were predicted using the "Drug-Disease" bioinformatic analysis. Furthermore, comprehensive network pharmacology and transcriptomic approaches were employed to investigate the underlying mechanisms of GPE in the treatment of liver disease. RESULTS: The pathological examinations showed that GPE significantly alleviated hepatocyte necrosis and liver injury. GPE significantly downregulated Bax and cleaved-PARP expression and upregulated Bcl-2 expression during CCl4-induced hepatocyte apoptosis. We compared the effects of four typical compounds in GPE -a ginsenoside (Rb3) shared by both GPE and ginseng and three unique gypenosides in GPE. Notably, Gypenoside A (GPA), a unique saponin in GPE, markedly reduced hepatocyte apoptosis. In contrast, ginsenoside Rb3 had a weaker effect. Network pharmacology and transcriptomic analyses suggested that this anti-apoptotic effect was achieved by upregulating the PI3K/Akt signaling pathway mediated by PDK1. CONCLUSIONS: These results suggested that G. pentaphyllum had a promising hepatoprotective effect, with its mechanism primarily involving the upregulation of the PDK1/Bcl-2 signaling pathway by GPA, thereby preventing cell apoptosis.

Liver histological changes in untreated chronic hepatitis B patients in indeterminate phase.

BACKGROUND: Studies with large size samples on the liver histological changes of indeterminate phase chronic hepatitis B (CHB) patients were not previously conducted. AIM: To assess the liver histological changes in the indeterminate phase CHB patients using liver biopsy. METHODS: The clinical and laboratory data of 1532 untreated CHB patients were collected, and all patients had least once liver biopsy from January 2015 to December 2021. The significant differences among different phases of CHB infection were compared with t-test, and the risk factors of significant liver histological changes were analyzed by the multivariate logistic regression analysis. RESULTS: Among 1532 untreated CHB patients, 814 (53.13%) patients were in the indeterminate phase. Significant liver histological changes (defined as biopsy score ≥ G2 and/or ≥ S2) were found in 488/814 (59.95%) CHB patients in the indeterminate phase. Significant liver histological changes were significant differences among different age, platelets (PLTs), and alanine aminotransferase (ALT) subgroup in indeterminate patient. Multivariate logistic regression analysis indicated that age ≥ 40 years old [adjust odd risk (aOR), 1.44; 95% confidence interval (CI): 1.06-1.97; P = 0.02], PLTs ≤ 150 × 109/L (aOR, 2.99; 95%CI: 1.85-4.83; P < 0.0001), and ALT ≥ upper limits of normal (aOR, 1.48; 95%CI: 1.08, 2.05, P = 0.0163) were independent risk factors for significant liver histological changes in CHB patients in the indeterminate phase. CONCLUSION: Our results suggested that significant liver histological changes were not rare among the untreated CHB patients in indeterminate phase, and additional strategies are urgently required for the management of these patients.

[Clinical value of acoustic radiation force impulse imaging for quantitative evaluation of degree of liver fibrosis in chronic hepatitis C patients].

OBJECTIVE: To investigate the diagnostic value of acoustic radiation force impulse (ARFI) imaging technology for the assessment of liver fibrosis in chronic hepatitis C (CHC) patients. METHODS: One-hundred-and-eight CHC patients were examined by real-time ultrasound elastography using the Acuson S2000 ARFI instrument (Siemens Healthcare) and underwent liver biopsy for pathohistological analysis. The correlation between liver fibrosis grades determined by the two approaches was analyzed. The cut-off values for diagnosis by ARFI (S more than 2, S more than 3 and S = 4) were determined by generating a receiver operating characteristic (ROC) curve. RESULTS: The spectrum of liver stiffness detected by ARFI sonoelastography included S1 at (1.26+/-0.27) m/s (n = 36), S2 at (1.45+/-0.51) m/s (n = 31), S3 at (2.01+/-0.54) m/s (n = 27), and S4 at (2.28+/-0.82) m/s (n = 14). The ARFI values were significantly different among the four different stages of liver fibrosis (P less than 0.001). The liver stiffness detected by ARFI sonoelastography was significantly correlated with the liver fibrosis stage determined by the gold standard pathohistological analysis (Spearman's rank coefficient: 0.61, P less than 0.001). Using the ARFI technology for assessment of liver fibrosis gave areas under the ROC curve of 0.779 for S more than 2 patients, of 0.863 for S more than 3 patients, and of 0.0880 for S = 4 patients. CONCLUSION: The real-time ultrasound elastography ARFI technology can show the elasticity modulus of liver, and its data values positively correlate with the patho-histology grade of liver fibrosis in CHC patients. ARFI technology is easy to operate, non-invasive, and quantitative, and has potential clinical value for assessing liver fibrosis in CHC.

The Challenging Path to Diagnosing Extraintestinal Amoebiasis: A Case Report of an HIV-Infected Patient.

Background: Amoebiasis, an infectious disease caused by the parasitic protozoan E. histolytica, is easily misdiagnosed due to its declining incidence and atypical symptoms. Case Presentation: A 31-year-old male presented to the hospital with dyspnea and inability to lie flat. Imaging studies indicated a large amount of pleural effusion on the right side and multiple huge cysts in the liver. The patient underwent liver tumor resection surgery at another hospital due to suspected malignancy, but no evidence of relevant malignant tumors was found in the pathological examination. Subsequently, we performed metagenomic next-generation sequencing on the liver drainage fluid and obtained liver pathology slides from the hospital where the surgery was performed at that time. Both of them confirmed the diagnosis of amoebic infection. Empirical treatment with metronidazole was initiated before the diagnosis was confirmed, along with symptomatic treatments such as thoracic drainage and liver drainage. Eventually, the patient's condition improved and he was discharged smoothly. Conclusion: In order to avoid misdiagnosis of amoebiasis, thoroughly inquiring about the patient's medical history, shifting perspectives and continuing investigating are necessary when one diagnostic approach proves ineffective. Besides, interdisciplinary collaboration and persistent efforts are crucial for accurate diagnosis.

Unpaired virtual histological staining using prior-guided generative adversarial networks.

Fibrosis is an inevitable stage in the development of chronic liver disease and has an irreplaceable role in characterizing the degree of progression of chronic liver disease. Histopathological diagnosis is the gold standard for the interpretation of fibrosis parameters. Conventional hematoxylin-eosin (H&E) staining can only reflect the gross structure of the tissue and the distribution of hepatocytes, while Masson trichrome can highlight specific types of collagen fiber structure, thus providing the necessary structural information for fibrosis scoring. However, the expensive costs of time, economy, and patient specimens as well as the non-uniform preparation and staining process make the conversion of existing H&E staining into virtual Masson trichrome staining a solution for fibrosis evaluation. Existing translation approaches fail to extract fiber features accurately enough, and the decoder of staining is unable to converge due to the inconsistent color of physical staining. In this work, we propose a prior-guided generative adversarial network, based on unpaired data for effective Masson trichrome stained image generation from the corresponding H&E stained image. Conducted on a small training set, our method takes full advantage of prior knowledge to set up better constraints on both the encoder and the decoder. Experiments indicate the superior performance of our method that surpasses the previous approaches. For various liver diseases, our results demonstrate a high correlation between the staging of real and virtual stains (ρ=0.82; 95% CI: 0.73-0.89). In addition, our finetuning strategy is able to standardize the staining color and release the memory and computational burden, which can be employed in clinical assessment.

Adult diffuse hepatic hemangiomatosis: A case report and review of the literature.

Diffuse hepatic hemangiomatosis (DHH) is an extremely rare disease, especially in adults. We present a case of DHH involving the entire liver in a 62-year-old male with a giant hemangioma next to the superior mesenteric vein. Based on what we could find in PubMed with pathological evidence, there are only seventeen cases of adult DHH reported in the literature. The female-to-male ratio is 2.4:1. Most patients consult for abdominal pain or distension. Radiographic examination shows multiple diffuse liver nodules. On MRI, these lesions show hypointense T1 and hyperintense T2. Some lesions may show peripheral rim enhancement in the arterial phase but no portovenous washout. In total, 47% of patients with DHH have one or more giant hemangioma(s). Pathology shows that the lesions are lined with flat endothelial cells without cellular atypia, which are stained positive for vascular endothelial markers. Liver failure is the main cause of death. Some patients can be improved by partial hepatectomy. However, there is no effective treatment for most patients. Liver transplantation should be considered in patients with liver failure or congestive heart failure caused by DHH. We attempt to classify DHH into two types based on the distribution of DHH and their treatment.

Spike-mediated ACE2 down-regulation was involved in the pathogenesis of SARS-CoV-2 infection.

The ongoing global pandemic of Coronavirus disease 2019 (COVID-19) poses a serious threat to human health, with patients reportedly suffering from thrombus, vascular injury and coagulation in addition to acute and diffuse lung injury and respiratory diseases. Angiotensin converting enzyme 2 (ACE2) as the receptor for SARS-CoV-2 entry, is also an important regulator of renin-angiotensin system (RAS) homeostasis, which plays an unsettled role in the pathogenesis of COVID-19. Here, we demonstrated that SARS-CoV-2 Spike protein activated intracellular signals to degrade ACE2 mRNA. The decrease of ACE2 and higher level of angiotensin (Ang) II were verified in COVID-19 patients. High dose of Ang II induced pulmonary artery endothelial cell death in vitro, which was also observed in the lung of COVID-19 patients. Our finding indicates that the downregulation of ACE2 potentially links COVID-19 to the imbalance of RAS.

Gd-EOB-DTPA-enhanced MRI-a noninvasive and short-term assessment method for liver necroinflammation after direct-acting antiviral (DAA) therapy in patients with chronic hepatitis C.

PURPOSE: To assess liver necroinflammation in HCV patients undergone antiviral therapy by Gd-EOB-DTPA-enhanced MRI with histopathologic analyses as reference. METHODS: HCV patients were enrolled in this prospective study before antiviral treatment between 09-2016 and 07-2017. Unenhanced MR, Gd-EOB-DTPA-enhanced MR, and liver biopsy were performed before and 24 weeks after treatment of daclatasvir with asunaprevir (DAA). DWI was obtained using a breath-hold single-shot echo planar spin-echo sequence. Twenty minutes after administration of Gd-EOB-DTPA, the relative enhancement (RE) and the contrast enhancement index (CEI) were recorded. Liver necroinflammatory activity grades (G0-18) were categorized on the Ishak Scoring systems. CEI, RE, and DWI of baseline and 24 weeks after treatment were compared by paired t test. Relationship between MR parameters and histologic scores was evaluated by Pearson's correlation. Receiver operating characteristic analysis evaluated the measurements' diagnostic performance. MRI variability between two readers was assessed using the intraclass correlation coefficient.Results RESULTS: A decrease of liver necroinflammatory activity grade (p < 0.0001) was detected in final cohort (n = 21; mean age 44 years; 23 to 67 years; 11 F, 10 M). Statistical results of 42 person-times in 21 patients at baseline and follow-up showed CEI and ADC were significantly different (p = 0.006 and 0.036) across histologic grades of liver necroinflammation. Significant increase of CEI, RE, and ADC (p = 0.0004, 0.0032, 0.0110) 24 weeks after DAA treatment was seen. Additionally, CEI was correlated to necroinflammatory grade (r = - 0.596, p = 0.006). AUROC for CEI, ADC, and CEI combined with ADC to differentiate patients with none and mild (G0-6) from patients with moderate and severe necroinflammation (G7-18) was 0.834 (95% CI 0.712-0.956, 0.724(95% CI 0.565-0.884) and 0.837(95% CI 0.717-0.956). CONCLUSION: Gd-EOB-DTPA-enhanced MRI by CEI could be used as a noninvasive imaging biomarker to distinguish grades of necroinflammatory activity in patients with HCV after DAAs therapy at early stage and CEI combined with ADC could get a better diagnostic accuracy.

Corticosteroid plus glycyrrhizin therapy for chronic drug- or herb-induced liver injury achieves biochemical and histological improvements: a randomised open-label trial.

BACKGROUND: Treatment of chronic drug-induced liver injury (DILI) or herb-induced liver injury(HILI) is an important and unresolved challenge. There is no consensus regarding the indications for corticosteroids for chronic DILI/HILI. AIMS: To investigate the efficacy and safety of corticosteroid plus glycyrrhizin for patients with chronic DILI/HILI. METHODS: This was a randomised open-label trial. Eligible patients with causality assessment using the updated RUCAM were randomly assigned (1:1) either to the steroid treatment group (48-week stepwise dose reduction of methylprednisolone plus glycyrrhizin) or control group (glycyrrhizin alone). Liver biopsies were performed at baseline and at the end of the 48-week treatment period. The primary outcome was the proportion of patients with sustained biochemical response (SBR). The secondary outcomes were improvement in liver histology, time to biochemical normalisation and safety. RESULTS: Of 80 participants, 70 (87.5%) completed the trial. The patients were predominantly female (77.5%), aged >40 years (77.5%) and had a hepatocellular injury pattern of DILI (71.2%). Compared to the control group, the treatment group showed a higher proportion of SBR (94.3% vs. 71.4%, p = 0.023), shorter biochemical normalisation time and histological improvements in both histological activity and fibrosis. The DILI and HILI subgroups, as well as the autoimmune hepatitis (AIH)-like DILI and non-AIH-like subgroups, showed comparable responses. No severe adverse events were observed during the trial. CONCLUSION: This study provides the first clinical evidence that corticosteroid plus glycyrrhizin therapy for chronic DILI with or without AIH-like features can achieve both biochemical response and histological improvements with good safety. (ClinicalTrials.gov, NCT02651350).

Altered biliary epithelial cell and monocyte responses to lipopolysaccharide as a TLR ligand in patients with primary biliary cirrhosis.

OBJECTIVE: Lipopolysaccharide (LPS) is suspected to trigger primary biliary cirrhosis (PBC) in susceptible individuals, yet the precise mechanism of its effect in PBC remains largely unknown. The aim of this study was to investigate altered responses to LPS ligand for Toll-like receptors (TLRs) in pathogenesis of PBC in vivo and in vitro. MATERIAL AND METHODS: In vivo, we investigated levels of LPS and pro-inflammatory cytokines in sera and expression of LPS receptors in liver tissues from 162 patients with PBC, 325 patients with other liver diseases and 80 healthy controls. In vitro, altered responses to LPS on monocytes and cultured human biliary epithelial cells (BECs) from patients with PBC were determined. RESULTS: Significantly higher levels of LPS in patients with PBC were detected, compared with patients with other liver diseases and healthy controls. Immunohistochemically, expression of TLR4, CD14, CD68 and NF-κB was significantly enhanced in liver tissues from patients with PBC. Before LPS stimulation, we found significantly higher serum levels of tumor necrosis factor-α, interleukin (IL)-1ß, IL-6 and IL-8 in patients with PBC than those in healthy controls. After LPS stimulation, TLR4 expression and pro-inflammatory cytokine production in CD14-positive monocytes and cultured BEC from patients with PBC increased significantly. CONCLUSIONS: These results indicated that patients with PBC were prone to exhibit higher serum LPS level, hypersensitivity of monocytes and BEC to LPS, and enhanced production of pro-inflammatory cytokines. LPS altered expression of TLR4, CD14 and NF-κB on monocytes and BEC, which may be implicated in the pathogenesis and progression of PBC.

The LAC Score Indicates Significant Fibrosis in Patients With Chronic Drug-Induced Liver Injury: A Large Biopsy-Based Study.

Currently, there are no satisfactory noninvasive methods for the diagnosis of fibrosis in patients with chronic drug-induced liver injury (DILI). Our goal was to develop an algorithm to improve the diagnostic accuracy of significant fibrosis in this population. In the present study, we retrospectively investigated the biochemical and pathological characteristics of consecutive patients with biopsy-proven chronic DILI, who presented at our hospital from January 2013 to December 2017. A noninvasive algorithm was developed by using multivariate logistic regression, receiver operating characteristic (ROC) curves, and decision curve analysis (DCA) to diagnose significant fibrosis in the training cohort, and the algorithm was subsequently validated in the validation cohort. Totally, 1,130 patients were enrolled and randomly assigned into a training cohort (n = 848) and a validation cohort (n = 282). Based on the multivariate analysis, LSM, CHE, and APRI were independently associated with significant fibrosis. A novel algorithm, LAC, was identified with the AUROC of 0.81, which was significantly higher than LSM (AUROC 0.78), CHE (AUROC 0.73), and APRI (AUROC 0.68), alone. The best cutoff value of LAC in the training cohort was 5.4. When the LAC score was used to diagnose advanced fibrosis and cirrhosis stages, the optimal cutoff values were 6.2 and 6.7, respectively, and the AUROC values were 0.84 and 0.90 in the training cohort and 0.81 and 0.83 in the validation cohort. This study proved that the LAC score can contribute to the accurate assessment of high-risk disease progression and the establishment of optimal treatment strategies for patients with chronic DILI.

Analysis of pathological changes in the epithelium in COVID-19 patient airways.

Severe COVID-19 patient airways plugged by MUC5AC-containing mucus exhibit hyperplasia of goblet cells, and hypoplasia of multiciliated cells and club cells, as well as significantly reduced CC16 and MUC5B levels, and increased IL-13 levels https://bit.ly/2M2NcdO.

TREM-2 is a sensor and activator of T cell response in SARS-CoV-2 infection.

Limited understanding of T cell responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has impeded vaccine development and drug discovery for coronavirus disease 2019 (COVID-19). We found that triggering receptor expressed on myeloid cells 2 (TREM-2) was induced in T cells in the blood and lungs of patients with COVID-19. After binding to SARS-CoV-2 membrane (M) protein through its immunoglobulin domain, TREM-2 then activated the CD3ζ/ZAP70 complex, leading to STAT1 phosphorylation and T-bet transcription. In vitro stimulation with M protein-reconstituted pseudovirus or recombinant M protein, and TREM-2 promoted the T helper cell 1 (TH1) cytokines interferon-γ and tumor necrosis factor. In vivo infection of CD4­TREM-2 conditional knockout mice with murine coronavirus mouse hepatitis virus A-59 showed that intrinsic TREM-2 in T cells enhanced TH1 response and viral clearance, thus aggravating lung destruction. These findings demonstrate a previously unidentified role for TREM-2 in SARS-CoV-2 infection, and suggest potential strategies for drug discovery and clinical management of COVID-19.