Differences in clinical characteristics among 726 patients with Chinese herbal medicine- or Western medicine-induced liver injury.

The differences between Chinese herbal medicine (CHM)- and Western medicine (WM)-induced liver injury have rarely been reported. Our aim was to investigate the clinical features of patients with drug-induced liver injury (DILI) caused by CHM or WM. The medical records of 726 DILI patients were retrospectively collected at Peking University First Hospital from January 1995 through August 2019. The number of inpatients with DILI in our hospital showed an increasing trend over time. The incidence of DILI caused by CHM exhibited a linear trend toward an increase with time (P = .0012). Of the 726 DILI patients, females accounted for 65.8%. There were 353 cases (48.6%) caused by CHM and 225 cases (40.0%) caused by WM. The 3 most common causative CHMs were Polygonum multiflorum (38 cases), Fructus Psoraleae (35 cases), and Epimedium (26 cases). The proportions of female patients, alanine aminotransferase (ALT) levels, aspartate aminotransferase (AST) levels, total bilirubin (TBIL) levels and antinuclear antibody (ANA) positivity rates among cases caused by CHM were higher than those of cases caused by WM (P < .05). There were more patients with severe cases caused by CHM than with severe cases caused by WM (P < .05). The clinical characteristics of DILI caused by CHM differ from those caused by WM. The incidence of DILI caused by CHM is increasing yearly. The medication time of DILI caused by CHM is longer than that of DILI caused by WM, and the severity is greater. Therefore, it is necessary to scientifically and rationally use traditional CHM and monitor liver function. For DILI caused by CHM, the CHM prescription should be recorded in detail to provide detailed clinical data for scientific research on the liver toxicity of CHM.

Evaluation of the tumoricidal efficacy of adoptive cell transfer using hepatocellular carcinoma-derived organoids.

Background: Tumor-derived organoid, namely tumoroid, can realistically retain the clinicopathologic features of original tumors even after long-term in vitro expansion. Here we develop this production methodology derived from hepatocellular carcinoma primary samples and generate a platform to evaluate the tumoricidal efficacy of autologous adoptive cell transfer including tumor infiltrating lymphocytes and peripheral blood lymphocytes. Methods: Haematoxylin and eosin together with immunohistochemistry staining were employed to ascertain the morphologic and histological features of tumoroids and original tumors. Tumor killing ability of T cells was detected by lactate dehydrogenase assay and propidium iodide staining. In tumoroid xenograft mouse model, tumor volumes were measured and T cell functions were examined by flow cytometry technique. Results: Four tumoroids with characteristics of poor differentiation and mild fibrosis were successfully established from fourteen hepatocellular carcinoma samples. More robust antitumor potential and hyper-functional phenotype of all four tumor infiltrating lymphocytes were observed compared to matched peripheral blood lymphocytes in coculture system. In tumoroid xenograft mouse models, however, only one patient-derived tumor infiltrating lymphocytes with the highest antitumor activity can bestow efficient tumor eradication. Conclusions: Hepatocellular carcinoma tumoroid-based models could represent invaluable resources for evaluating the tumoricidal efficacy of autologous adoptive cell transfer. Tumor infiltrating lymphocytes should be a promising and yet-to-be-developed regimen to treat hepatocellular carcinoma.

Discharge may not be the end of treatment: Pay attention to pulmonary fibrosis caused by severe COVID-19.

Since December 2019, coronavirus disease (COVID-19) has rapidly swept the world. So far, more than 30 million people have been infected and nearly one million have died. Although the world is still in the stage of COVID-19 pandemic, the treatment of new cases and critically ill patients is the focus of the current work. However, COVID-19 patients lead to pulmonary fibrosis, such a serious threat to the prognosis of complications were also worthy of our attention. First of all, we proposed the possible mechanism of pulmonary fibrosis caused by SARS-CoV-2, based on the published data of COVID-19 ((i) Direct evidence: pulmonary fibrosis was found in autopsy and pulmonary puncture pathology. (ii) Indirect evidence: increased levels of fibrosis-related cytokines[transforming growth factor [TGF]- ß, tumor necrosis factor [TNF]- α, interleukin [IL]-6, etc] in peripheral blood of severe patients.) What is more, we summarized the role of three fibrosis-related signaling pathways (TGF- ß signal pathway, WNT signal pathway and YAP/TAZ signal pathway) in pulmonary fibrosis. Finally, we suggested the therapeutic value of two drugs (pirfenidone and nintedanib) for idiopathic pulmonary fibrosis in COVID-19-induced pulmonary fibrosis.

Single-nucleotide polymorphisms of HLA and Polygonum multiflorum-induced liver injury in the Han Chinese population.

BACKGROUND: Polygonum multiflorum is one of the leading causes of herb-induced liver injury in China. HLA-B*35:01 is reported to be a potential biomarker of Polygonum multiflorum-induced liver injury (PM-DILI). However, little is known about the relationship between single-nucleotide polymorphisms (SNPs) and PM-DILI. AIM: To identify SNPs that indicate susceptibility to PM-DILI. METHODS: We conducted a systematic study enrolling 382 participants from four independent hospitals, including 73 PM-DILI patients, 118 patients with other drug-induced liver injury (other-DILI) and 191 healthy controls. Whole-exome sequencing was performed for 8 PM-DILI patients and 8 healthy controls who were randomly selected from the above subjects. Nineteen SNPs that showed high frequencies in the 8 PM-DILI patients were selected as candidate SNPs and then screened in 65 PM-DILI patients, 118 other-DILI patients and 183 healthy controls using the MassARRAY system. HLA-B high-resolution genotyping was performed for the 73 PM-DILI and 118 other-DILI patients. The Han-MHC database was selected as a population control for HLA-B analysis. P < 6.25 × 10-3 after Bonferroni correction was considered significant. RESULTS: The frequencies of rs111686806 in the HLA-A gene, rs1055348 in the HLA-B gene, and rs202047044 in the HLA-DRB1 gene were significantly higher in the PM-DILI group than in the control group [27.2% vs 11.6%, P = 1.72 × 10-5, odds ratio (OR) = 3.96, 95% confidence interval (CI): 2.21-7.14; 42.5% vs 8.6%, P = 1.72 × 10-19, OR = 13.62, 95%CI: 7.16-25.9; 22.9% vs 8.1%, P = 4.64 × 10-6, OR = 4.1, 95%CI: 2.25-7.47]. Only rs1055348 showed a significantly higher frequency in the PM-DILI group than in the other-DILI group (42.5% vs 13.6%, P = 1.84 × 10-10, OR = 10.06, 95%CI: 5.06-20.0), which suggested that it is a specific risk factor for PM-DILI. rs1055348 may become a tag for HLA-B*35:01 with 100% sensitivity and 97.7% specificity in the PM-DILI group and 100% sensitivity and 98.1% specificity in the other-DILI group. Furthermore, HLA-B*35:01 was confirmed to be associated with PM-DILI with a frequency of 41.1% in the PM-DILI group compared with 11.9% (P = 4.30 × 10-11, OR = 11.11, 95%CI: 5.57-22.19) in the other-DILI group and 2.7% (P = 6.22 × 10-166, OR = 62.62, 95%CI: 35.91-109.20) in the Han-MHC database. CONCLUSION: rs111686806, rs1055348, and rs202047044 are associated with PM-DILI, of which, rs1055348 is specific to PM-DILI. As a tag for HLA-B*35:01, rs1055348 may become an alternative predictive biomarker of PM-DILI.

Deficiency of canonical Wnt/ß-catenin signalling in hepatic dendritic cells triggers autoimmune hepatitis.

BACKGROUND & AIMS: Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease manifested with the aberrant activation of hepatic dendritic cells (HDCs) and the subsequent breakdown of immune homeostasis. As an important player, HDC maintains immunological balance between tolerance to self-antigens versus destruction against pathogens in liver. However, the intracellular signalling networks that program HDC remain unclear. We have now found the role of canonical Wnt/ß-catenin signalling in HDCs. METHODS: Liver sections from AIH patients and healthy subjects were stained for the markers of Wnt/ß-catenin signalling. Concanavalin A (ConA) and HDC/Hepa1-6 vaccine-induced AIH mouse models were examined for liver injury, inflammation and immune cell functions by serum biochemistry, histology, quantitative reverse transcription polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assay (ELISA) and flow cytometry analysis. Wnt/ß-catenin signalling expression was measured using immunoblot and qRT-PCR. RESULTS: Canonical Wnt/ß-catenin signalling in HDC is deficient in AIH patients and a mouse model, which coincides with the immunogenic function of HDCs. Furthermore, Wnt ligand engagement reactivates Wnt/ß-catenin signalling and recovers the immunoregulatory phenotype of HDCs, in turn alleviating the severity of AIH. Likewise, pharmacologic activation of Wnt/ß-catenin signalling attenuates AIH progression. CONCLUSIONS: We report here that the constitutively active canonical Wnt/ß-catenin signalling confers HDCs tolerogenicity under steady-state conditions. Deficiency of this pathway gives rise to T cell-mediated immune response and incidence of AIH. It may act as a new pathogenesis and treatment target for AIH.

A human ciliopathy with polycystic ovarian syndrome and multiple subcutaneous cysts: A rare case report.

RATIONALE: Ciliopathies is a group of clinically and genetically overlapping disorders due to cilia abnormalities and multiple organ systems are involved in. PATIENT CONCERNS: We present a young female patient who showed renal function impairment, Caroli syndrome (CS), liver cirrhosis, polycystic ovarian syndrome, and multiple subcutaneous cysts. DIAGNOSES: The patient was diagnosed with ciliopathy according to the clinical manifestations and whole-genome sequencing. INTERVENTIONS: She received treatment of intravenous albumin, polyene phosphatidyl choline, furosemide, and antisterone. OUTCOMES: The patient showed clinical improvement in her edema and liver tests, and ultrasonography revealed that the ascites had disappeared. Unfortunately, the edema relapsed a year later. The patient received the same treatment as before, and there was clinical improvement of the edema. Since the family cannot afford liver and kidney transplantation, the patient only accepted symptomatic treatment. LESSONS: Polycystic ovarian syndrome and multiple subcutaneous cysts have never before been reported to be associated with ciliopathy. This finding could remind doctors to consider the possibility of ciliopathy disease for patients suffering from similar conditions. In addition, the phenotype of the patient differs from those of patients reported with the same mutations, which also reminds doctors that the clinical manifestation of a given mutation may show patient-specific differences. This case report extends the phenotypic spectrum of ciliopathy, and these findings might represent a new ciliopathy syndrome, which could facilitate the diagnosis of ciliopathies.