Abnormal Liver Function Research Articles

Antibiotic-Associated Drug-Induced Liver Injury in Critically Ill Children: A Prospective Observational Study

INTRODUCTION. Drug-induced liver injury (DILI) is associated, among other things, with the use of antibiotics. Children with DILI are at risk of acute liver failure and even death. However, the literature on the subject provides little information on the possibility of distinguishing the types of hepatic lesions to diagnose potentially life-threatening DILI in time.AIM. The study aimed to describe the phenotype of new-onset DILI associated with antibiotics in critically ill children with nosocomial infection.MATERIALS AND METHODS. The authors conducted a prospective observational study in the resuscitation and intensive care units of the Morozov Children’s City Clinical Hospital from 1 February 2020 to 1 September 2021. The study assessed the incidence of antibiotic-associated DILI using the Global Trigger Tool. The study enrolled 100 critically ill children aged 0 to 17 years (44 boys and 56 girls) with nosocomial infection.RESULTS. Signs of hepatotoxicity were detected in 19 patients, including 8 with abnormal liver function tests but normal liver function and 11 with abnormal liver function tests and clinically apparent liver disease. Thus, the incidence of new-onset hepatotoxicity associated with antibiotics amounted to 12.9 cases per 100,000 paediatric patients, and the incidence of DILI was 7.5 cases per 100,000 children. Based on the analysis of medical records, biochemical findings, and relationships between the time of dosing and the manifestation of signs of liver disorder in 11 children, the authors characterised the phenotype of idiosyncratic cholestatic hepatitis. Critically ill children treated with antibiotics showed alanine transaminase activity up to 10 times the upper limit of normal (ULN), bilirubin levels up to 4.45 times the ULN, and gamma-glutamyl transferase activity up to 5 times the ULN. The odds of developing new-onset DILI were the highest with tigecycline (OR: 4.07; 95% CI: 1.32–12.50) and meropenem (OR: 1.84; 95% CI: 1.01–3.36). In 6 patients, clinical signs of idiosyncratic cholestatic hepatitis resolved within a few weeks after antibiotic discontinuation. The other 5 patients with clinical signs of idiosyncratic cholestatic hepatitis died.CONCLUSIONS. The authors described the phenotype of idiosyncratic cholestatic liver injury associated with antibiotics in critically ill children. The role of pharmacogenetic markers in the development of DILI associated with antibiotics in critically ill children needs to be assessed further to implement a risk-based approach and mitigate the risks.The study was registered at ClinicalTrials.gov under No. NCT04141657 on 24 October 2019.

Liver function tests at admission as marker of severity and prognosis in COVID-19 patients - A retrospective analysis.

With evolving pandemic, a substantial proportion of patients are presenting with liver dysfunction as an extra-pulmonary manifestation of COVID-19 illness. We planned this study to evaluate the incidence of liver dysfunction in COVID-19 pneumonia and find an association between abnormal liver function and the severity of the disease. We retrospectively analysed the hospital records of 344 patients with moderate to severe COVID-19 illness admitted to a Dedicated COVID Hospital in North India. Out of 344 patients included in the study, 59.9% were males. The abnormal liver functions were present in 78.49% of patients at admission. Mean age of the patient with liver dysfunction was 53.41 ± 15.71 years. The incidence of elevated aspartate aminotransferase (AST), alanine aminotransferase (ALT), and hypoalbuminemia was 82.96%, 74.91%, and 69.7%, respectively, in patients with COVID-19 at admission. A positive correlation was found between the levels of AST, ALT and hypoalbuminemia with severity of disease. Mortality was 33% in patients with liver dysfunction in comparison to 18.9% in patients with normal liver functions. More than 75% of the patient had abnormal liver functions at admission, and mortality was also high in this group. Mortality can be effectively reduced if laboratory parameters such as elevated AST and ALT and hypoalbuminemia are closely monitored at admission and during hospital stay in patients with risk factors like male, age <55 years and HTN.

PATTERN OF LIVER DYSFUNCTION AMONG ANTENATAL WOMEN ATTENDING OPD OF A TERTIARY CARE CENTER

Background: Liver disorders in pregnancy encompass a spectrum of diseases encountered during antenatal and postnatal period resulting in abnormal liver function tests and hepatobiliary dysfunction or both. This study is aimed at determining the pattern of liver disorders during pregnancy. Methods:One hundred patients with liver disorders during pregnancy during the period of one year were included. Data was recorded in Excel workbook and analyzed. Results:91% of the women had liver disorders peculiar to pregnancy while 7% of the women had liver diseases which were coincidental to pregnancy while 2 women had preexisting liver disease. Our study observed that 2 women had chronic hepatitis. Five percent of the women had hepatitis B and 2% had chronic hepatitis C infection. Forty percent of the women had preeclampsia, 26% had cholestasis, and 2% had acute liver failure. The most common antepartum complication was gestational hypertension and pre-eclampsia (34% followed by IUGR (17%). Conclusions:Liver disease has deleterious effect on pregnancy outcome with increased maternal and foetal morbidity and mortality. Timely diagnosis by proper antenatal check-up, early interventions and intensive monitoring of both mother and fetus with the teamwork of obstetrician, physician, gastroenterologist, and anaesthetist can prevent and reduce feto-maternal morbidity and mortality.

Selpercatinib-induced hepatotoxicity: A rare case report

Abstract Introduction/Objective Selpercatinib (Retevmo) is a highly selective rearranged during transfection (RET) kinase inhibitor indicated for treatment of solid tumors with RET gene mutation or fusion, such as medullary thyroid carcinoma or non-small cell lung carcinoma. Among selpercatinib’s side effects, severe hepatotoxicity was only seen in 3% of the patients. Here we report a case of selpercatinib-induced hepatotoxicity, which has not been well characterized before. Methods/Case Report The patient was a 56-year-old female who had medullary thyroid carcinoma with RET M918T mutation (pT3aN1b) status post total thyroidectomy. Recurrence occurred and selpercatinib treatment was initiated. Then the patient complained of mouth sores, tongue sensitivity, and lower extremity cramping. The dosage was reduced to half. The magnetic resonance imaging on day 67 of selpercatinib treatment showed heterogeneous enhancement in the right hepatic lobe, compatible with parenchymal liver disease/hepatitis, trace perihepatic ascites, and mild splenomegaly. On day 71, liver function abnormalities were detected (ALK 315 IU/L, ALT 745 IU/L, AST 899 IU/L, total bilirubin 7.7 mg/dL). Workups including autoimmune hepatitis serology, viral hepatitis, or other infections were all negative. She had no history of other drug use. On day 72, a liver biopsy was performed that demonstrated mild to moderate portal lymphocyte-predominant mixed inflammation with interface activity. The lobules showed marked inflammation with hepatocyte disorganization, acidophil bodies, hepatocyte dropout, and rare lipogranulomas. Bile duct injury and patchy canalicular cholestasis were also noted. Trichrome stain showed focal bridging fibrosis. Overall, the histologic findings were acute and chronic hepatitis pattern injury, favor selpercatinib-induced hepatotoxicity. Selpercatinib was discontinued. All liver enzymes gradually returned to normal levels on day 169. Results (if a Case Study enter NA) NA Conclusion Our study suggests that screening patients for abnormal liver function tests prior to and monitoring periodically during selpercatinib treatment is necessary. Based on the severity of hepatotoxicity, withholding, reducing the dose, or permanently discontinuing selpercatinib is recommended.

A Fatal Case of Hemophagocytic Lymphohistiocytosis Triggered By Babesiosis

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a rare condition characterized by hyperactivation of macrophages and T lymphocytes. While HLH is primarily inherited in a recessive manner among children, in adults, it is more commonly associated with underlying infections, autoimmune disorders, and malignancies. However, the association between HLH and Babesia infection remains exceptionally uncommon, with only a few reported cases in the medical literature. In this report, we present a unique case of HLH in the context of babesiosis, shedding light on the crucial clinical features and risk factors. By raising awareness of this rare differential diagnosis, we aim to contribute to early recognition and timely treatment, potentially reducing mortality from this treatable illness. Case Presentation: A 77-year-old male with history of deep vein thrombosis (DVT), Parkinson's disease, and lumbar radiculopathy on chronic prednisone, presented for progressive generalized weakness, leg pain, and confusion. Initial labs showed normocytic anemia, thrombocytopenia, low fibrinogen and elevated INR and liver enzymes (Table 1). Multiple ischemic signs were noted including acute on chronic DVT, as well as findings of marked splenomegaly with wedge infarcts and periportal lymphadenopathy on abdominal ultrasound and CT (Figure 1). The underlying etiology of these findings was unclear and broad differential work up was pursued. Given the anemia and thrombocytopenia on presentation, the patient received multiple blood products including platelets, red blood cells, fresh frozen plasma and cryoprecipitate, in addition to vitamin K. No schistocytes were seen peripherally, and DIC/TTP workup was negative. Multidisciplinary teams evaluated the risk versus benefit of anticoagulation with heparin drip considering evidence of multi-organ ischemic damage. It was briefly initiated, but later held due to persistent thrombocytopenia and abnormal liver function. Further work up only revealed hemolysis with a low haptoglobin and elevated LDH (Table 1). However, the follow up Coombs test was negative, ruling out immune mediated hemolysis. While symptomatic management continued, blood parasite screen obtained on admission indicated Babesia microti infection. Upon repeat testing, no evidence of babesia was identified on labs or blood smear. However, this finding was skewed by the multiple transfusions the patient received. Unfortunately, the clinical course rapidly declined, and the patient's family elected a transition to comfort care measures whereby the patient expired within two days of presentation. Remaining work up resulted posthumously, with CD25 levels elevated at 38,354.0 pg/mL. Coupled with the previously established splenomegaly, pancytopenia, hypertriglyceridemia, and elevated ferritin, these findings indicate a diagnosis of HLH, likely triggered by Babesia microti infection. Conclusion: HLH should be strongly suspected in patients from endemic regions, especially with additional risk factors such as age, genetics, and immunosuppression. Tools such as the HScore and the HLH-2004 criteria can aid in further patient risk stratification. Urgent treatment with steroids and addressing underlying babesiosis with atovaquone, azithromycin, and potentially red blood cell exchange transfusion, remains crucial for preventing decompensation and improving outcomes.

Comparison between Hetrombopag and Eltrombopag Combined with IST As First-Line Treatment for Severe Aplastic Anemia

Idiopathic aplastic anemia is a primary bone marrow failure disease that manifests with pancytopenia. Standard IST combined with eltrombopag (EPAG) is recommended as a first-line regimen for severe aplastic anemia patients who are ineligible for HSCT. HPAG is also a small molecule non-peptide TPO-RA developed in China, and the preclinical experiments have demonstrated that hetrombopag (HPAG) can promote the proliferation and differentiation of hematopoietic stem cells and the strength of stimulation was superior to eltrombopag. HPAG also can achieve hematological response for over 40% of IST-refractory SAA patients, and it was approved for use in IST-refractory SAA patients in China in 2021. Our previous report showed that as a first-line treatment, it could improve the HR and CR rate of SAA patients by 68.7% and 34.4% within 6 months, but there has yet to be a report on its efficacy compared to EPAG. Therefore, this study aims to evaluate the difference in early treatment efficacy of SAA patients with HPAG/EPAG combined with IST as first-line therapy. A total of 109 patients were included in this study, with a median age of 38 years, 53 male and 56 female. Among them, 67 patients received treatment with HPAG combined with ATG+CSA, and 42 patients received treatment with EPAG combined with ATG+CSA. The median follow-up time for the HPAG group was 13.7 (8.1-19.6) months, with a median usage duration of 12 (9.4-14.5) months. For the EPAG group, the median follow-up time was 22.5 (9.9-30.5) months, with a median usage duration of 13.5 (7.8-18.7) months. At 3 months, 34 (50.7%) cases in the HPAG group achieved HR, including 9 (13.4%) CR. In the EPAG group, 21 (50%) cases achieved HR, including 5 (11.9%) CR. The HR rates in the HPAG group after 3 months of IST were similar to those in the EPAG group, with no statistically significant difference ( P=0.973). At 6 months, there were no differences in HR and CR between the HPAG and EPAG groups, 65.6% vs 73.8% and 31.3% vs 28.6%, respectively ( P=0.494 and 0.452). The median time to first response in the HPAG group was similar to the EPAG group [3.7 (95% CI: 3.1-6) months vs 3.5 (95% CI: 3.2-6) months, P=0.79]. We further compared the efficacy of TPO-RA combined with IST in patients with different severity of disease. The results showed that the HR and CR of patients with VSAA at 3 and 6 months in the HPAG group were no different compared to that in the EPAG group (HR at 3 and 6 months, 22.2% vs 35.7% and 33.3% vs 57.1%, P=0.671 and 0.404, respectively; CR at 3 and 6 months, 11.1% vs 14.3% and 16.7% vs 28.6%, P=1.000 and 1.000, respectively). In the patients with SAA, the HR, and CR at 3 and 6 months in the HPAG group were comparable to that in the EPAG group (HR, 61.2% vs 57.1% and 77.6% vs 82.1%, P=0.883 and 0.557, respectively; CR, 14.3% vs 10.7% vs 36.7% vs 28.6%, P=1.000 and 0.486, respectively). In the multivariable analysis, for all 109 patients, the acquisition of HR at 6 months was unrelated to TPO-RA types, and positively correlated with higher HGB and PLT levels and PNH positivity, while negatively correlated with disease severity and ALC levels. Baseline PLT levels were the only predictive factor for EPAG group patients to achieve HR 6 months after IST. The acquisition of HR in HPAG group patients after IST was negatively correlated with disease severity and ALC levels, and positively correlated with baseline PNH positivity. Overall, both HPAG and EPAG have good safety profiles, and no patients discontinued treatment due to adverse drug reactions. Abnormal liver function is a concern for both drugs and changes in the main liver function indicators (AST, ALT, DBIL, IBIL) at 3 and 6 months after IST. Among them, significant increases in indirect bilirubin levels were observed in patients using EPAG at 3 and 6 months ( P&amp;lt;0.001), while no significant increases in indirect bilirubin levels were observed in the HPAG group. Overall, HPAG added to standard IST can provide SAA patients with similar efficacy to EPAG, while achieving deeper and faster hematological responses. Moreover, the hepatic safety of HAPG may be superior to EPAG. However, this study is a retrospective study with a small number of cases, and large-scale prospective clinical studies are still needed to verify the results.

Efficacy and Safety of Chidamide Combined with BEAM Conditioning Regimen in Autologous Transplantation for T-Cell Lymphoma

Background: T cell lymphoma (TCL) is a group of highly heterogeneous aggressive non-Hodgkin lymphomas with different pathogenesis and clinical prognosis. Despite the survival benefits of anthracycline-based chemotherapy bridging autologous stem cell transplantation (ASCT), 40% to 50% of TCL patients fail to respond to treatment and relapse or die within a short period of time. Chidamide is an oral selective histone deacetylase inhibitor (HDACi), interferes with epigenetic regulation by deacetylating nuclear transcription factors, affects proliferation and differentiation of tumor cells, and regulates cytokines in the tumor microenvironment. Chidamide combined with chemotherapy has promising clinical applications in ASCT. Aims: This prospective Phase II trial aims to evaluate the efficacy and safety of chidamide in combination with carmustine, etoposide, cytarabine, and melphalan (Chi-BEAM) conditioning regimen in ASCT of TCL patients received CR/PR to first-line chemotherapy. Method: In this study, eligible patients with TCL (except IPI 0-1 ALK+ anaplastic large cell lymphoma) aged 18-65 years were enrolled. All patients received Chi-BEAM conditioning regimen before ASCT. 30mg of chidamide was administered twice a week for at least 2 years after ASCT.The primary end point was 2-year progression-free survival (PFS) rate, and the secondary end points were 2-year overall survival (OS) rate and safety evaluation. Results: At the time of data cut off, a total of 18 patients were enrolled, with a median age of 48 (15-65) years. The 1-year PFS rate and OS rate after ASCT were 90.0% and 100.0%, respectively. The median implantation time of neutrophils was 10 days (9-13 days), and the median implantation time of platelets was 17 days (11-25 days). Most of the adverse reactions (AEs) were tolerable, including controlled grain deficiency with fever, electrolyte disturbance, and abnormal liver function. Conclusion: Chidamide combined with BEAM as a conditioning regimen for ASCT can significantly improve PFS and OS in TCL patients, and the AEs are controllable. The study is ongoing and further results will be continuously released.

Longitudinal PET/CT Imaging with Iodine ( 124I) Evuzamitide Reveals Organ Response to Plasma Cell Immunotherapy in a Patient with AL Amyloidosis

Background:Iodine-124-evuzamitide is a novel amyloidophilic peptide (p5+14), labeled with iodine-124, for detecting amyloid by positron emission/x-ray computed tomographic (PET/CT) imaging ( Pharmaceuticals 2023 Apr 21;16(4):629). PET is an inherently quantitative modality and thus 124I-evuzamitide may be useful for monitoring disease progression and response to therapy. Amyloid deposits can impact any organ in patients with light chain-associated amyloidosis (AL); thus, tissue-specific changes in amyloid load, based on PET/CT imaging, may be informative. Currently, response to therapy is assessed by anatomic imaging and measurement of serum or urinary biomarkers. However, the correlation between these metrics and concomitant changes in amyloid load remains enigmatic. Here, we report a case of a patient with AL amyloidosis, on long-term daratumumab therapy, who underwent longitudinal 124I-evuzamitide PET/CT imaging over 4 years (NCT03678259 and NCT05968846). Patient and Methods: A 70-year-old male presented with abnormal liver function tests, notably an elevated serum alkaline phosphatase (ALK) of 465 IU/L. Biopsies of both the liver and celiac nodes revealed the characteristic apple-green birefringence of Congo red stain, indicating the presence of amyloid. The patient began daratumumab immunotherapy 14 months prior to his enrollment in the 124I-evuzamitide imaging study and over the 4-year course of serial imaging. During this time, regular serial serum biomarkers were evaluated as standard of care. PET/CT images were acquired at 0, 23, and 45 months. For each imaging session, the patient received 2 mCi iodine-124-labeled tracer via intravenous injection and was imaged at 5 h post injection. Image data were assessed for visual uptake of radiotracer and quantified by manual 2D region-of-interest analysis where the semi-quantitative mean standard uptake value ratio (SUVR mean) was calculated using blood pool as the reference tissue. Results: Over the 45 months of evaluation, there was a 59% and 73% reduction in 124I-evuzamitide SUVR in the liver and spleen. This was accompanied by decreases in the weight-scaled organ volume (cc/kg) for both the liver (15.2%) and spleen (30.0%) based on segmentation of the organ volume from CT images. This reduction in radiotracer uptake coincided with a sustained decrease in serum FLC, from 38.3 mg/L to 19.1 mg/L, and a positive liver response, where ALK levels dropped from ~200 IU/L to ~120 IU/L. In contrast, renal radiotracer uptake increased slightly in the context of stable creatinine levels, and a modest decline in eGFR. Cardiac uptake of 124I-evuzamitide remained positive and relatively stable, concordant with serum NT-proBNP levels. These data suggest that organ-specific amyloid response, in the context of a sustained hematologic response, may occur independently and at different rates. Conclusion: Previous reports have demonstrated the resolution of AL amyloid. However, this is the first report using an amyloid-binding radiotracer, capable of visualizing all major organs including the heart, demonstrating the complex pattern of organ response and regression of AL amyloid in the context of concurrent biomarker improvement and changes in organ volume. PET/CT imaging using 124I-evuzamitide may, therefore, play a valuable role in both diagnosing amyloidosis and monitoring changes in organ-specific amyloid load. Additional longitudinal imaging studies are needed to support this clinical application.

A Preliminary Report of Clinical Study on Immunosuppressive Therapy Combined with Avatrombopag As the First-Line Treatment for Severe Aplastic Anaemia in Elderly Patients

Objective The objective is to evaluate the early hematologic response (HR) rate and safety of immunosuppressive therapy (IST) combined with avatrombopag as the first-line treatment for severe/very sever aplastic anaemia(V/SAA) in elderly patients. Methods Prospective，multi-center, single-arm, clinical research. IST treatment regimen: pig anti-human lymphocyte globulin (ALG-p, Wuhan Institute of Biological Products Co., Ltd. China) 20 mg/kg/d for five days and cyclosporin A (CsA) 3 mg/kg/d with adjusted concentration of 150-250 ng/mL, and oral avatrombopag 40 mg/d from the first day of IST initiation up to six months. The patients' treatment responses were evaluated and the major adverse events were collected. Results Ten patients have been enrolled in the study at our centre from June 2022 to October 2022.Among 10 patients, six had SAA and four had VSAA; male: female = 1:1, median age of 68 (60-82) years, and median time from diagnosis to treatment of 44 (20-480) days. The patients' treatment responses were evaluated after initiation of IST, at 3 months: 7 HR [1 complete response (CR), 3 good partial response (GPR), 3 partial response (PR), and 3 no response (NR)]; and at 6 months: 8 HR (1 CR, 5 GPR, 2 PR) and 2 deaths due to infection. The median time of red-cell transfusion independence was 60 (3-168) days in HR patients and that of platelets was 60 (16-153) days. No relapse and clonal evolution occurred within six months. Major adverse events within three months were infection in five cases, electrolyte disturbance in five cases, and cardiac insufficiency in three cases. Liver function abnormalities occurred in two cases, both of which showed elevated alanine aminotransferase up to 174 μ/L and 208.7 μ/L on day 8 and 20 of IST treatment, respectively. Two of the five infected patients had sepsis caused by Enterobacter cloacae. Except for infection, the remaining adverse events were of grade I-II. All the adverse events were effectively controlled. Table 1 summarises the characteristics and clinical status of patients before and after the treatment. Conclusion This preliminary study of IST combined with avatrombopag for the treatment of elderly patients with V/SAA showed the potential of the combination to improve haematologic response rate and quality in elderly patients with AA, and it is well tolerated as well. Keywords: immunosuppressive therapy, severe aplastic anaemia, avatrombopag, elderly

Effect of Hetrombopag Combined with Rhtpo in Patients with Severe Immune Thrombocytopenia

Background: Severe Immune Thrombocytopenia (ITP) is a life-threatening acquired hemorrhagic disease with dramatically decreased platelet number and clinical bleeding symptoms. Some patients with severe ITP did not respond to first-line treatment including steroids and Intravenous Immunoglobulin (IVIG). It was critical for them to use effective treatments to promote platelet and reduce the risk of fatal bleeding. Clinical practice guidelines have recommended the use of thrombopoietin receptor agonist (TPO-RA) as a second-line treatment for ITP. Recombinant human thrombopoietin (rhTPO) and hetrombopag are two distinct TPO-RAs with different mechanisms. As reported, there remains no study assessing the efficacy and safety of hetrombopag combined with rhTPO in the treatment of ITP. Therefore, the present study aimed to investigate the efficacy of hetrombopag plus rhTPO in Chinese patients with severe ITP, focusing on the short rather than the long-term efficacy, such as quickly increasing platelet count and significantly reducing bleeding, which would be more meaningful for severe patients whose platelet count &amp;lt;10 × 10 9/L. Methods: This was a prospective, open-label, single-center study with a planned enrollment of 30 patients. The inclusion criteria were patients ≥ 18 years, diagnosed with primary immune thrombocytopenia, platelet count &amp;lt;10 × 10 9/L, or bleeding score ≥ 5. Patients receiving other ITP drugs as maintenance therapy were eligible if previous glucocorticoid therapy doses were stable, and rituximab was used for at least 2 months and other immunosuppressants were stable for at least 4 weeks. Patients who had received IVIG, avatrombopag, eltrombopag, or romiplostim within 2 weeks prior to enrollment were excluded. Histories of platelet transfusion one week before treatment were excluded. Hetrombopag was given at 5 mg/day for 28 days, while rhTPO was administered at 300 U/kg subcutaneously daily for 14 days. When PLT &amp;gt; 100 × 10 9/L, rhTPO should be discontinued. When PLT &amp;gt; 150 × 10 9/L, the dosage of hetrombopag was reduced to 2.5mg/day, and it would be discontinued if PLT &amp;gt; 250 × 10 9/L. The primary endpoints were proportion of subjects with platelet count ≥30×10 9/L and at least doubled the baseline platelet count within 28 days. Secondary endpoints included bleeding score, incidence of thrombotic events, and adverse events (AEs). Results: As to July 27, 2023, a total of 20 patients were included in this study, with a median age of 36 years and a male proportion of 50%. Among them, 70% (14 cases) were newly diagnosed ITP patients. 50% of patients have received ≥ 1 line of previous treatment, of which 2 patients have received IVIG treatment and both have achieved CR (PLT ≥ 100 × 10 9/L). The baseline median platelet count was 5 × 10 9/L, and 95% (19 cases) of patients had active bleeding with a bleeding score of ≥ 1 point. The median duration for hetrombopag at dose of 5mg is 8.0 days, and rhTPO is 6.5 days. After combined treatment, the median time for platelet counts reached 30, 50, and 100 × 10 9/L was 4.5 days, 6 days, and 7 days, respectively. Among them, the median platelet count reached 103 × 10 9/L after 7 days treatment and 214.5 × 10 9/L after 15 days. Within 15 days of combined treatment, 15% (3 cases) of patients achieved partial platelet reaction (PLT &amp;gt; 50 × 10 9/L, without bleeding), and 85% (17 cases) achieved complete platelet reaction (PLT &amp;gt; 100 × 10 9/L, without bleeding). In terms of safety, two patients experienced liver function abnormalities, both of which were grade 1-2. One was related to treatment drugs, and the other was associated with underlying autoimmune liver disease. No thrombotic events occurred in all patients. Conclusion: This study innovatively explores the efficacy and safety of combination therapy with hetrombopag and rhTPO in the treatment of severe ITP. It is preliminarily confirmed that this combination therapy can effectively and quickly improve the early platelet response of ITP patients, avoid bleeding damage, and is expected to become a new treatment choice for severe ITP patients. We also look forward to the overall efficacy evaluation results of all patients after completing treatment in the future.

Incidence, Interpretation and Management of Liver Function Abnormalities in Patients with Chronic Myeloid Leukemia (CML) Treated with Tyrosine Kinase Inhibitors (TKI)

Background: Hepatotoxicity is a well-recognised side effect of tyrosine kinase inhibitors (TKI) and in some patients it can be a challenge to find a well-tolerated and effective drug. Isolated hyperbilirubinemia is common but, particularly in the case of nilotinib, is generally attributed to concomitant Gilbert's syndrome, characterized by the reduced expression of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). We have previously reported hyperbilirubinemia in association with the homozygous Gilbert genotype in patients treated with imatinib, dasatinib and nilotinib and have now extended our studies to more recent TKI. In addition we have analysed the incidence of TKI-associated transaminitis and attempted to identify safer alternative TKI. Methods: From our database of &amp;gt;900 patients presenting with CML CP1 from 2000-2022 and treated with a TKI, we identified 467 individuals who had received only TKI (prior interferon, combination experimental therapy, auto- and allografted patients all excluded), had normal liver function tests (LFT) at TKI start and for whom serial consecutive LFT were available. Variations in dinucleotide repeats in the UGT1A1 promoter region were analyzed by PCR with genotypes: 6/6 (homozygous for (TA) 6 allele; wild-type), 7/7 (homozygous for (TA) 7 allele) and 6/7 (heterozygous). Because individual patients could receive more than one TKI, we defined the period on treatment with each TKI as an ‘episode’ so as to attribute abnormal LFT to a specific drug. Abnormal LFT were graded according to the CTCAE version 4.0 and any occurrence of abnormalities was cross-checked to exclude a confounding reason (e.g. antibiotics, cholecystitis). Patients were censored at last LFT. Results: 229 females and 238 males (median age at diagnosis 47 yrs (range 11-90) had 955 separate TKI episodes: imatinib 406, dasatinib 222, nilotinib 189, bosutinib 87, ponatinib 28 and asciminib 23. The median number of LFT per patient was 47 (range 3-264). 7 UGT1A1 genotypes were identified, of which 45%, 41% and 13% were wild type 6/6, heterozygous 6/7 and homozygous 7/7 respectively (6 patients with other genotypes excluded). With the exception of asciminib, hyperbilirubinemia was more frequent in homozygous patients for all TKI. It was also common in all patients treated with nilotinib but in wild type and heterozygous patients, was frequently associated with concomitant transaminitis. A close temporal relationship between start of TKI and raised bilirubin suggests causality (Fig 1a-d). The incidences of transaminitis of any grade were 44%, 47%, 65%, 66%, 43% and 39%, and of &amp;gt;grade 1 were 7%, 8%, 17%, 32%, 18% and 13% for imatinib, dasatinib, nilotinib, bosutinib, ponatinib and asciminib respectively. Of 202 patients with a transaminitis on first line TKI, 94 were subsequently switched to a 2 nd line TKI, and 27 of those to a 3 rd line TKI. Irrespective of the TKI used, recurrent transaminitis of any grade was common occurring in 60/94 (64%) on 2 nd line and 19/27 (71%) on 3 rd line, although abnormalities &amp;gt;grade 2 were unusual (&amp;lt;1% on 2 nd line, &amp;lt;5% on 3 rd line). 179 patients developed transaminitis on imatinib, 46 and 29 switched (rarely for transaminitis) to dasatinib and nilotinib respectively. 28 (61%) on dasatinib and 23 (79%) on nilotinib had a second transaminitis (dasatinib - 14% &amp;gt;grade 1, nilotinib - 22% &amp;gt;grade 1)). Of 227 patients without transaminitis on imatinib, 63 and 67 switched to dasatinib or nilotinib. 28 (44%) on dasatinib and 38 (57%) on nilotinib developed further transaminitis (dasatinib - 0% &amp;gt;grade 1, nilotinib 19% &amp;gt;grade1). With respect to identifying a ‘safer’ drug we studied in detail 15 patients with grades 3-4 transaminitis on 1 st line therapy; imatininb-10, dasatinib-1, nilotinib-3, bosutinib -1. Four settled on dose reduction, and of the remaining 11, 7 returned to normal or maximum grade 1 on dasatinib. Conclusion: With the exception of asciminib the previous association of TKI, homozygous Gilbert and hyperbilirubinemia was confirmed. Grade 1 transaminitis is common on all TKIs, with higher grades of severity most frequent on bosutinib. Patients experiencing abnormal transaminases on 1 st line TKI are likely to have similar problems on 2 nd and 3 rd line agents, with a trend to higher incidence/severity on nilotinib compared to dasatinib.

Association between the sarcopenia index and abnormal liver function in the adult population in the United States: a cross-sectional study

BackgroundThe objective of this study was to explore the association between the sarcopenia index and abnormal liver function in adult individuals in the United States.MethodologyThis study employed a rigorous cross-sectional analysis of data derived from the National Health and Nutrition Examination Survey (NHANES) conducted between 2017 and 2018. The primary objective was to investigate the correlation between the sarcopenia index and abnormal liver function. To achieve this, an advanced multivariate regression model was utilized, allowing for comprehensive analysis and meticulous adjustment of relevant variables. To ensure the robustness of the findings, a visually appealing smooth curve was constructed, and a two-stage regression model was applied for validation. Additionally, a detailed gender-stratified analysis was conducted to further explore the association between the sarcopenia index and abnormal liver function within distinct subgroups.ResultsThrough our rigorous participant selection process, a total of 1756 individuals were included in the study. The meticulously adjusted multivariate regression model revealed a significant negative association between the sarcopenia index and abnormal liver function, with an adjusted odds ratio (OR) of 0.73 and a 95% confidence interval (CI) ranging from 0.63 to 0.86. The robustness of this association was further supported by the visually appealing smooth curve plot. Moreover, in the gender-stratified subgroup analysis, after meticulous adjustment for confounding factors, notable differences in this association emerged (males: OR = 0.8, 95% CI: 0.66–0.98; females: OR = 0.61, 95% CI: 0.47–0.79).ConclusionThis cross-sectional study yields robust evidence indicating a negative correlation between the sarcopenia index and abnormal liver function, predominantly observed among females.

Hepatitis E Virus Infection Caused Elevation of Alanine Aminotransferase Levels in a Patient with Chronic Hepatitis B and Choledocholithiasis

Hepatitis E virus (HEV) genotypes 3 and 4 are zoonotic strains that are primarily transmitted through the consumption of undercooked pork or game meat. They also cause asymptomatic infections, acute hepatitis, acute-on-chronic liver failure, chronic hepatitis, and extrahepatic manifestations. Here, we report a man in his 80s who had chronic hepatitis B, took entecavir for it, and presented with higher levels of alanine aminotransferase (ALT) and jaundice. An abdominal computed tomography scan revealed choledocholithiasis with cholecystolithiasis. Although endoscopic papillary balloon dilatation was performed for the removal of a common bile duct stone, the abnormal liver function tests, including jaundice, were prolonged. After other viral hepatitis and other causes of the liver injury were ruled out, as his serum was positive for immunoglobulin A anti-HEV and HEV genotype 3b RNA, we diagnosed him as having acute hepatitis E. In this case, with chronic hepatitis B and a common bile duct stone, the prolonged abnormal results for the liver function tests seemed to be caused by HEV infection. In conclusion, in cases with high ALT levels after removing choledocholithiasis, other factors, including HEV infection, should be considered to determine the cause of abnormal liver function test results. The further examination of hepatitis D virus infection and high ALT levels may be needed in HBV-infected individuals.

Efficacy and safety of molnupiravir in patients with Omicron variant vaccine breakthrough COVID-19 infection: a randomized, controlled trial.

Introduction: Randomized, controlled trials of molnupiravir in real-world use during the Omicron wave are scarce. The frequency of hospitalization and death is low, so further research is needed to confirm the virological efficacy of molnupiravir. Methods: A single-center, randomized, controlled clinical trial was conducted, and 111 hospitalized coronavirus disease 2019 (COVID-19) patients were randomly assigned at a ratio of 1:1. Fifty-three patients in the molnupiravir group were administered 800mg of molnupiravir twice daily for 5 days in addition to the standard therapy, and 58 patients in the control group only received the standard therapy in accordance with local guidelines. The antiviral effect and adverse events were evaluated during the follow-up. Results: The median viral clearance time in the molnupiravir group was significantly shorter than that in the control group (p = 0.003). Furthermore, patients who started molnupiravir therapy within 3 days had significantly shorter viral clearance time than the controls (p = 0.003). In the vaccinated subgroup, molnupiravir therapy was also associated with a shorter viral clearance time (p = 0.003). A total of three adverse events, which were minor, were reported in the molnupiravir group. One of the patients had mild liver function abnormalities, and all of them were resolved without intervention. However, the remission time was similar between the two tested groups. Conclusion: Molnupiravir exhibited good viral replication inhibitor efficacy in patients with Omicron variant vaccine breakthrough COVID-19 infection. Clinical Trial Registration: [https://www.chictr.org.cn/], identifier [ChiCTR2200059796].

Phenotype and genotype characteristics of children with cardiomyopathy associated with MYH7 gene mutation: a retrospective analysis

To investigate the clinical phenotype and genotype characteristics of children withcardiomyopathy (CM) associated with MYH7 gene mutation. A retrospective analysis was conducted on the medical data of five children with CM caused by MYH7 gene mutation who were diagnosed and treated in the Department of Cardiology, Hebei Children's Hospital. Among the five children with CM, there were three girls and two boys, all of whom carried MYH7 gene mutation. Seven mutation sites were identified, among which five were not reported before. Among the five children, there were three children with hypertrophic cardiomyopathy, one child with dilated cardiomyopathy, and one child with noncompaction cardiomyopathy. The age ranged from 6 to 156 months at the initial diagnosis. At the initial diagnosis, two children had the manifestations of heart failure such as cough, shortness of breath, poor feeding, and cyanosis of lips, as well as delayed development; one child had palpitation, blackness, and syncope; one child had fever, runny nose, and abnormal liver function; all five children had a reduction in activity endurance. All five children received pharmacotherapy for improving cardiac function and survived after follow-up for 7-24 months. The age of onset varies in children with CM caused by MYH7 gene mutation, and most children lack specific clinical manifestations at the initial diagnosis and may have the phenotype of hypertrophic cardiomyopathy, dilated cardiomyopathy or noncompaction cardiomyopathy. The children receiving early genetic diagnosis and pharmacological intervention result in a favorable short-term prognosis.

Air pollution associate with advanced hepatic fibrosis among patients with chronic liver disease.

We aimed to investigate the association between air pollution and advanced fibrosis among patients with metabolic associated fatty liver disease (MAFLD) and chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. A total of 1376 participants who were seropositive for HBV surface antigen (HBsAg) or antibodies to HCV (anti-HCV) or had abnormal liver function in a community screening program from 2019 to 2021 were enrolled for the assessment of liver fibrosis using transient elastography. Daily estimates of air pollutants (particulate matter ≤2.5 μm in diameter [PM2.5 ], nitrogen dioxide [NO2 ], ozone [O3 ] and benzene) were aggregated into mean estimates for the previous year based on the date of enrolment. Of the 1376 participants, 767 (52.8%) and 187 (13.6) had MAFLD and advanced fibrosis, respectively. A logistic regression analysis revealed that the factors associated with advanced liver fibrosis were HCV viremia (odds ratio [OR], 3.13; 95% confidence interval [CI], 2.05-4.77; p < 0.001), smoking (OR, 1.79; 95% CI, 1.16-2.74; p = 0.01), age (OR, 1.04; 95% CI, 1.02-1.05; p < 0.001) and PM2.5 (OR, 1.10; 95% CI, 1.05-1.16; p < 0.001). Linear regression analysis revealed that LSM was independently correlated with PM2.5 (β: 0.134; 95% CI: 0.025, 0.243; p = 0.02). There was a dose-dependent relationship between different fibrotic stages and the PM2.5 level (the PM2.5 level in patients with fibrotic stages 0, 1-2 and 3-4: 27.9, 28.4, and 29.3 μg/m3 , respectively; trend p < 0.001). Exposure to PM2.5 , as well as HBV and HCV infections, is associated with advanced liver fibrosis in patients with MAFLD. There was a dose-dependent correlation between PM2.5 levels and the severity of hepatic fibrosis.

COVID-19-associated liver injury: Adding fuel to the flame.

COVID-19 is mainly characterized by respiratory disorders and progresses to multiple organ involvement in severe cases. With expansion of COVID-19 and SARS-CoV-2 research, correlative liver injury has been revealed. It is speculated that COVID-19 patients exhibited abnormal liver function, as previously observed in the SARS and MERS pandemics. Furthermore, patients with underlying diseases such as chronic liver disease are more susceptible to SARS-CoV-2 and indicate a poor prognosis accompanied by respiratory symptoms, systemic inflammation, or metabolic diseases. Therefore, COVID-19 has the potential to impair liver function, while individuals with preexisting liver disease suffer from much worse infected conditions. COVID-19 related liver injury may be owing to direct cytopathic effect, immune dysfunction, gut-liver axis interaction, and inappropriate medication use. However, discussions on these issues are infancy. Expanding research have revealed that angiotensin converting enzyme 2(ACE2) expression mediated the combination of virus and target cells, iron metabolism participated in the virus life cycle and the fate of target cells, and amino acid metabolism regulated immune response in the host cells, which are all closely related to liver health. Further exploration holds great significance in elucidating the pathogenesis, facilitating drug development, and advancing clinical treatment of COVID-19-related liver injury. This article provides a review of the clinical and laboratory hepatic characteristics in COVID-19 patients, describes the etiology and impact of liver injury, and discusses potential pathophysiological mechanisms.

Chronic Hepatitis B Virus Infection and Risk of Stroke Types: A Prospective Cohort Study of 500 000 Chinese Adults.

Stroke is a leading cause of mortality and permanent disability in China, with large and unexplained geographic variations in rates of different stroke types. Chronic hepatitis B virus infection is prevalent among Chinese adults and may play a role in stroke cause. The prospective China Kadoorie Biobank included >500 000 adults aged 30 to 79 years who were recruited from 10 (5 urban and 5 rural) geographically diverse areas of China from 2004 to 2008, with determination of hepatitis B surface antigen (HBsAg) positivity at baseline. During 11 years of follow-up, a total of 59 117 incident stroke cases occurred, including 11 318 intracerebral hemorrhage (ICH), 49 971 ischemic stroke, 995 subarachnoid hemorrhage, and 3036 other/unspecified stroke. Cox regression models were used to estimate adjusted hazard ratios (HRs) for risk of stroke types associated with HBsAg positivity. In a subset of 17 833 participants, liver enzymes and lipids levels were measured and compared by HBsAg status. Overall, 3.0% of participants were positive for HBsAg. HBsAg positivity was associated with an increased risk of ICH (adjusted HR, 1.29 [95% CI, 1.16-1.44]), similarly for fatal (n=5982; adjusted HR, 1.36 [95% CI, 1.16-1.59]) and nonfatal (n=5336; adjusted HR, 1.23 [95% CI, 1.06-1.44]) ICH. There were no significant associations of HBsAg positivity with risks of ischemic stroke (adjusted HR, 0.97 [95% CI, 0.92-1.03]), subarachnoid hemorrhage (adjusted HR, 0.87 [95% CI, 0.57-1.33]), or other/unspecified stroke (adjusted HR, 1.12 [95% CI, 0.89-1.42]). Compared with HBsAg-negative counterparts, HBsAg-positive individuals had lower lipid and albumin levels and higher liver enzyme levels. After adjustment for liver enzymes and albumin, the association with ICH from HBsAg positivity attenuated to 1.15 (0.90-1.48), suggesting possible mediation by abnormal liver function. Among Chinese adults, chronic hepatitis B virus infection is associated with an increased risk of ICH but not other stroke types, which may be mediated through liver dysfunction and altered lipid metabolism.

Non-targeted metabolomics reveals a modulatory effect of DHA-enriched phosphatidylserine in high fat-diet induced non-alcoholic fatty liver disease in mice

To investigate the regulatory mechanism of docosahexaenoic acid-enriched phosphatidylserine (DHA-PS) on high-fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD). The murine model was established by HFD or HFD combined with DHA-PS (100 mg/kg) administration for 10 weeks. DHA-PS administration notably improved HFD-induced abnormalities of liver function, lipid indices, inflammatory markers, and oxidative stress. In addition, based on non-targeted metabolomics, HFD notably disrupted the amino acid metabolism and fatty acid metabolism in murine liver tissue, while DHA-PS notably regulated the amino acid metabolism and PPAR signaling pathway to alleviate HFD-induced liver metabolic disorder. Moreover, results from Western blot and immunohistochemical analysis confirmed that DHA-PS alleviated HFD-induced NAFLD by regulating lipid metabolism and restraining the TLR4/NF-κB pathway. The results obtained suggest that DHA-PS might be used as a potential dietary supplement for alleviating HFD-induced NAFLD.

Endovascular treatment of postoperative hemorrhage after pancreatectomy: a retrospective study

BackgroundRuptured aneurysm is a serious complication of distal pancreatectomy (DP) or pancreatoduodenectomy (PD) that can be life-threatening if not treated promptly. This study aimed to examine the efficacy of a Viabahn stent graft for stopping bleeding after pancreatectomy.MethodsBetween April 2016 and June 2022, we performed 245 pancreatectomies in our institution. Six patients experienced postoperative bleeding and underwent endovascular treatment.ResultsAll six cases of bleeding occurred post-PD (3.7%). The bleeding was from gastroduodenal artery (GDA) pseudoaneurysms in three patients, and Viabahn stent grafts were inserted. All three patients did not show liver function abnormalities or hepatic blood flow disorders. One patient with a Viabahn stent graft experienced rebleeding, which required further management to obtain hemostasis. Of the six cases in which there was hemorrhage, one case of bleeding from the native hepatic artery could not be managed.ConclusionsUsing the Viabahn stent graft is an effective treatment option for postoperative bleeding from GDA pseudoaneurysms following PD. In most cases, using this device resulted in successful hemostasis, without observed abnormalities in hepatic function or blood flow.