Abnormal Liver Function Tests Research Articles

Metastatic Hepatic Epithelioid Hemangioendothelioma In 10 Years Old Boy; A Rare Case Report

OBJECTIVES Epithelioid Hemangioendothelioma is an infrequent vascular neoplasm of intermediate malignant potential oddly affecting children. It is primarily noted in soft tissues, the stomach, breast, spleen, brain, and liver. No definite risk factor is identified in children. However, following WWTR1-CAMTA1 and YAP1-TFE3 gene fusions are frequently seen in these tumours. We present a case of very rare childhood Epithelioid Hemangioendothelioma of the liver in a ten-year-old boy. A 10-year-old boy presented with abdominal pain, mild weight loss, and abnormal liver function tests. Radiologically, hepatic, pulmonary, and bony lesions are noted. The biopsy report showed Epithelioid Hemangioendothelioma confirmed by an Immunohistochemical panel. Due to the lack of facilities in our centre, palliative treatment was given to the patient. Surgical resection, liver transplant, and radiofrequency ablation were impossible due to widespread hepatic and pulmonary disease. The patient was resistant to any medical treatment. The patient died at the seventh-month follow-up. HEHE is a scarcely seen tumour with no definite management protocol. Surgical resection is the preferred treatment for resectable tumours. In non-resectable extensive bifocal tumours, like in our case, the preferred treatment is radio-frequency ablation and hepatic transplant. The overall survival is trivial due to the non-compliant nature of the disease.

Evaluating the Utility of Liver Transaminases as Predictors of Feto-Maternal Outcome in Lieu of Serum Bile Acids in Intrahepatic Cholestasis of Pregnancy: A Prospective Observational Study.

Intrahepatic Cholestasis of Pregnancy (ICP) is a disorder of the second half of pregnancy causing pruritus and abnormal liver function tests (LFT). Incidence in India is 1.2-1.5%. ICP leads to adverse feto-maternal outcomes with early delivery indicated before serum bile acids (SBA) (gold standard) and hepatic transaminases are critically high. With paucity of evidence these levels are not well defined. To determine the association of liver transaminases with pregnancy outcomes in ICP and evaluate critical levels for prediction of adverse outcomes. A prospective observational study was conducted comprising 88 pregnant women with pruritus not associated with rash. After history and examination, LFT and SBA levels were done, treatment given and followed till pregnancy termination to determine the feto-maternal outcome. The mean age of participants was 26.43 ± 3.35 years. The mean SBA, ALT and AST levels were 18.97 ± 10.320 μmol/L, 206.06 ± 45.71units/litre and 175.37 ± 101.088 units/litre respectively. 39.7% of participants were symptomatic for ICP while 38.6% responded to treatment. 34.1% underwent LSCS majorly (43.3%) formeconiumand 23.3% had foetal distress. 33% had preterm delivery. 5.68% of the neonates needed NICU admission and 6.8% had respiratory distress syndrome. The cut off for ALT on ROC curve analysis was 151.5 units/litre with AUC as 0.905, sensitivity and specificity of 89.7 and 70% respectively. ICP leads to adverse pregnancy outcomes. ALT is a promising predictor of adverse outcome and termination of pregnancy can be planned accordingly.

Liver dysfunction in children with scrub typhus: association with severity of illness and outcome

Background: Liver dysfunction is a common finding in children with scrub typhus. Adult literature has found a significant association between the extent of liver dysfunction and severity of illness and outcome. However, very few studies are available on children.Objectives: To study the extent of liver dysfunction in children with scrub typhus and its association with severity of illness and outcome.Method: It was a retrospective descriptive study conducted on children diagnosed with scrub typhus admitted to a tertiary care centre in south India from January 2016 to December 2020. Children from 1 month to 18 years of age were included. Demographic data, clinical details, laboratory parameters, course of illness and outcome data were collected and analysed. Results: Study population included 143 cases of scrub typhus. Mean age of the study population was 8.4 ± 4.4 years with a male: female ratio of 1.2:1. Fever was present in 100%, myalgia in 54.5%, decreased appetite in 54.5%, jaundice in 8.4% and hepatomegaly in 71.3% of children. Abnormal liver function tests were present in 75.5% children. Elevated aspartate transaminase (AST) was seen in 75.5%, elevated alanine transaminase (ALT) in 67.1%, hypoalbuminaemia in 47.5% and severe hypoalbuminaemia (<2.5g/dL) in 29.4%. Complications included meningitis (13.3%), shock (7.6%), meningoencephalitis (2.7%) and acute respiratory distress syndrome (2%). There were 2 (1.3%) deaths. Children with complications had higher AST (p <0.01), ALT (p = 0.018), low serum albumin (p<0.001) and prolonged international normalised ratio (INR) (p =0.003).Conclusions: Abnormal liver function tests were present in 75.5% of children with scrub typhus. Children with complications of scrub typhus had significantly higher median AST levels, ALT levels, low serum albumin levels and prolonged INR compared to children with no complications

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.

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.

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.

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 >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 >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 >grade 2 were unusual (<1% on 2 nd line, <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% >grade 1, nilotinib - 22% >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% >grade 1, nilotinib 19% >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.

No Place like Home: Home-Based Intravenous Arsenic Trioxide for the Treatment of Acute Promyelocytic Leukemia (APL)

Introduction: APL has transitioned from a highly fatal malignancy to a disease that is curable with a combination of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO). Intravenous (IV) administration of ATO remains the standard of care for consolidation, however, its use is associated with long infusion times, electrolyte disturbances, and QTc prolongation that has historically required frequent outpatient infusion center administration and monitoring. Following induction, patients receive a cumbersome schedule of ATO through daily infusions 5 days each week (typically Monday-Friday) 4 weeks on 4 weeks off for 4 cycles. Oral formulations of ATO are poorly water soluble, have not demonstrated adequate absorption in the gastrointestinal (GI) tract leading to significant GI upset and are not approved for use in the United States. Beginning in 2020, patients treated at our institution were given the option of receiving ATO at home through a partnership via Qualitas Specialty Pharmacy of RWJBarnabas Health. This retrospective review evaluates the feasibility, safety, and efficacy of administration of ATO in the home infusion setting for patients with APL receiving ATO consolidation. Methods: Through retrospective chart review, we evaluated patients who received consolidation therapy of ATO through home infusion from 2020-2023. Eligible patients included those with an ECOG of <2, absence of baseline QTc prolongation (defined as >500ms), and patients without significant kidney dysfunction or hepatotoxicity at baseline. We evaluated each patient for adverse effects such as QTc prolongation, electrolyte disturbances, liver function test (LFT) abnormalities, neutropenic fever, bacteremia, unplanned Emergency Room (ER) or urgent care visits, and unexpected hospitalizations (via Common Terminology Criteria for Adverse Events version 5). Results: Fifteen patients aged 19-79 (median = 43) were reviewed with 60% being male and 40% female. Sixty percent had a baseline ECOG 1 and 40% had an ECOG 0. Twenty percent of patients had a prior malignancy (n=3). Eighty percent of the patients experienced grade (gd) 1-3 electrolyte abnormalities (47% gd 1 hyperphosphatemia, 13% gd 1 hyperkalemia, 7% gd 2 hyperkalemia, 7% gd 3 hyperkalemia, 13% gd 1 hypokalemia, 13% gd 1 hypermagnesemia, 7% gd 3 hypermagnesemia, 7% gd 1 hypomagnesemia, 33% gd 1 hypernatremia, 33% gd 1 hyponatremia, & 7% gd 2 hyponatremia). Of the 15 patients receiving treatment, 27% experienced gd 1 alanine aminotransferase (ALT) increase, 13% of patients experienced gd 1 aspartate aminotransferase (AST) increase, and 7% of patients experienced gd 2 hyperbilirubinemia. For QTc prolongation, 53% of patients experienced gd 1 prolongation, 7% of patients experienced gd 2 prolongation, and 13% of patients experienced gd 3 prolongation. One out of the 15 patients experienced treatment delays due to QTc prolongation. While forty percent of patients visited either the ER and/or urgent care during consolidation therapy, no visits were deemed therapy related. Reasons for urgent evaluation included infections (n=3), vertigo (n=1), low back pain (n=1), facial numbness (n=1), fall (n=1), abdominal pain (n=1), and hemorrhoidal bleeding (n=1). Two patients were hospitalized, due to a renal infarct (n=1) and a subdural hematoma after a fall (n=1). None of the 15 patients experienced febrile neutropenia/bacteremia while receiving consolidation therapy. Of the 11 patients who completed consolidation at the time of this abstraction, all (100%) had complete remission demonstrated on post-consolidation bone marrow. One of the 11 patients relapsed within 6 months of consolidation; however, is now in remission following two additional consolidation courses and a bone marrow transplant. Four patients have not yet completed four cycles of ATO consolidation. One patient was transitioned from home infusion to clinic treatment due to out-of-pocket cost. Conclusions: Our study demonstrates that home infusion of ATO is both safe and highly effective for patients. Therapy was well tolerated with predictable and manageable toxicity. Prospective studies are needed to evaluate the efficacy and safety in comparison to patients receiving ATO in the infusion center as well as to assess patient-reported and cost outcomes. Given the safety profile of home-based ATO, we have implemented at home ATO consolidation as standard therapy for all eligible patients.

Clinical Features and Liver Function Tests in Non-ICU Hospitalized Patients with COVID-19 in University of Phayao Hospital

Background: SARS-CoV-2 has had a variety of symptoms, from mild to acute respiratory distress syndrome or multiple organ failure. Objective: To determine the epidemiological and clinical features of patients with COVID-19 who were admitted to non-intensive care unit (non-ICU) settings and to compare the results of liver function test (LFT) among different groups of non-ICU hospitalized patients with COVID-19. Materials and Methods: The retrospective cross-sectional study was conducted at the University of Phayao Hospital, Thailand. Patients diagnosed with COVID-19 and admitted to non-ICU wards between November 2021 and March 2022 were included. Descriptive data were analyzed using mean ± standard deviation or median (interquartile range), Pearson’s chi-square test, and analysis of variance (ANOVA). Results: Three hundred ninety-nine patients were included in the present study, with the median age of 30.2 years. Fifty-five percent of the patients were female, 45.9% had normal BMI, and 89% had no comorbidities. Common symptoms were non-productive cough in 62.4%, sore throat in 52.9%, and fever in 37.3%. Twenty-one patients (5.3%) were classified as Group 1, 311 patients (77.9%) were in Group 2, and 67 patients (16.8%) were in Group 3, according to the Ministry of Public Health of Thailand guidelines. Thirty-five percent of patients had LFT abnormalities on admission. Nine patients (2.2%) had chest X-ray abnormalities, of which five were found at the time of admission, and most had normal LFTs. Four patients who developed pulmonary infiltration during their hospital stay also had abnormal LFT afterward. No patients were transferred to the ICU, required vasopressors, needed mechanical ventilation during hospitalization, or died. Conclusion: The authors’ study provides clinical and LFT data on hospitalized, non-ICU COVID-19 patients in a single university hospital. These results also represent epidemiological value and guidance for treatment in the current endemic area. Keywords: COVID-19; Liver function test; Non-ICU hospitalized patients

The liver in sickle cell disease

Liver involvement in SCD patients is frequent but often misdiagnosed or underestimated, except in case of advanced liver diseases. Because of so far poorly recognized forms of chronic SCD-related vascular injury that can silently evolved towards end stages or facilitate ACLF, any persisting liver function tests abnormalities should be carefully investigated, following the above proposed algorithm. Work up and management must be considered multidisciplinary in relationship with a Hepatologist. Early SCD hepatopathy should prompt revision of SCD management to prevent further liver injury and decompensation, discussing transfusion exchanges and hydro urea when not yet initiated, and control for any cofactor of liver injury. The role of HSCT in early SCD hepatopathies also deserves evaluation. In advanced SCD hepatopathies, liver transplantation, which has been rarely performed so far, is the only therapeutic option associated with improved survival. It should definitely be discussed- either electively in case of decompensation in SCD cirrhosis or jaundice/recurrent cholangitis in cholestatic diseases, with excellent outcome, - or emergently in case of ALF or ACLF with more mitigate results.To improve knowledge and management of SCD liver diseases, creation of national and international registries, as well as longitudinal observational cohorts are encouraged.

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.

Phase 1b/2 Study Evaluating the Safety and Efficacy of Canakinumab with Darbepoetin Alfa in Patients with Lower-Risk Myelodysplastic Syndromes (MDS) Who Have Failed Erythropoietin Stimulating Agents (ESA)

Introduction: Pyroptosis is a form of inflammatory, caspase-1 dependent lytic cell death mediated by inflammasome activation and ultimately leading to enumeration of pro-inflammatory cytokines, particularly interleukin 1β (IL-1β) and is a key driver of MDS pathogenesis (Basiorka A, Blood 2016). Release of IL-1β by pyroptotic cells leads to paracrine stimulation of neighboring hematopoietic and stromal cells resulting in amplification of this circuit, myeloid derived suppressor cell (MDSC) accumulation as well as direct suppression of erythropoiesis. Thus, we investigated the combination of the IL-1β neutralizing antibody canakinumab in combination with darbepoetin in patients with ESA refractory lower risk MDS and present the final dose phase 1b data. Methods: Patients ≥ 18 years old with IPSS-R very low to intermediate risk MDS who were ESA refractory and hypomethylating agent (HMA) naïve with adequate organ function were eligible. Patients must have been RBC transfusion dependent or hemoglobin < 9 gm/dl with symptoms. Treatment consisted of subcutaneous (SC) canakinumab on day 1 of a 28 cycle (150mg dose level 1, 300mg dose level 2) and darbepoetin SC 300µg days 1 and 15 of each cycle for a total of 6 cycles with continuation of therapy for responding patients. The phase 1b portion utilized a 3+3 dose escalation design with 6 patients treated at the maximum tolerated dose (MTD) to define the recommended phase 2 dose (RP2D). Bone marrow (BM) disease assessments occurred every 3 cycles with response defined by IWG 2018 criteria. Quality of life was assessed by QUALMS (Abel A, Haematologica, 2016). Peripheral blood mononuclear cells (PBMCs) were obtained at disease assessments and day 15 of C1 for evaluation of adapter protein apoptosis associated speck-like protein containing a CARD (ASC) specks as a biomarker of inflammasome formation with quantification as previously described (McLemore A, Pyroptosis: Methods and Protocols, 2023). Total IL-1β of BM plasma was assayed by ELISA. Results: Nine patients enrolled with a median age of 71 (range: 61-85 years), 67% female with baseline IPSS-R, IPSS-M and mutation data shown in Table. By IPSS-M, 3, 3, 1, 2 patients were low, moderately-low, moderately high, and high-risk categories. All IPSS-M lower risk mutant patients had splicing mutations. The median number of mutations was 2 (range 0-5). 100% of patients were ESA refractory. Additionally, 33% and 56% were refractory to lenalidomide and luspatercept therapy, respectively. Eight (89%) patients were PRBC dependent at baseline (56% [n=5] with high transfusion burden). The median follow-up duration was 6.1 months (range 3-17.8). The most common adverse events were neutropenia (n=7), followed by thrombocytopenia (n=4), and abnormal liver function tests (n=4). There were two grade 3 adverse events including thrombocytopenia and colitis, both unrelated to study treatment. There were no dose-limiting toxicities or serious adverse events in the phase 1 portion. All patients achieved the best response as stable disease, and no one had progression disease. No patients achieved objective response or significant reduction in transfusion burden. There was no statistical improvement in total QUALMS score from baseline to end of treatment (P=0.72) nor in the individual components (i.e. physical burden, benefit finding and emotional burden, P=0.69, P=0.91, P=0.630; respectively) although several patients had individual improvements. The percentage of PBMCs with ASC specks at baseline ranged from 0.3945-2.978% (median 1.93%). ASC specks decreased significantly after cycle 1 of therapy and were durably suppressed over the course of treatment in a majority of patients (Figure). Extracellular IL-1β in bone marrow plasma robustly increased with treatment and remained elevated (representing non-functional IL-1β [canakinumab bound IL-1β]; P=0.002 cycle 6 versus baseline), supporting pharmacodynamic effect with no differences observed between DL1 and DL2. Conclusions: The combination of canakinumab and darbepoetin was safe and well tolerated and 300mg of canakinumab is the RP2D. Canakinumab inhibited inflammasome activation as evidenced by a reduction of ASC specks although this did not translate to clinical responses. Phase 2 of the study will focus on patients with lower transfusion burden and molecular subsets with highest IL-1β expression (e.g. TET2/ DNMT3A mutant).

Duvelisib for Cytokine Release Syndrome Prophylaxis during CD19-Targeted CAR T Cell Therapy

Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of patients with advanced non-Hodgkin lymphoma (NHL). However, treatment toxicity, including cytokine release syndrome (CRS) and immune cell-associated neurotoxicity syndrome (ICANS), can be significant. Effective prophylactic strategies may reduce the frequency and/or severity of CAR T cell therapy while also expanding the pool of patients eligible for such therapy. Duvelisib is an oral inhibitor of the gamma and delta isoforms of phosphoinositide 3-kinases (PI3K), which is an active therapy for CLL/NHL with an established safety profile. In addition, prior work from our group and others has demonstrated that PI3K inhibition can prevent CRS in an in vitro model (Amatya et al. ASH 2022) and can enhance antitumor cytotoxicity of CAR-T cells. Consequently, we performed a trial of duvelisib for CRS prophylaxis in patients undergoing standard-of-care (SoC) CAR T-cell therapy for NHL (NCT05044039). This was a phase I trial with a 3 + 3 dose escalation and two-arm dose expansion phase. The trial enrolled patients with NHL eligible for SoC CAR T-cell therapy and adequate organ function. Herein, we report data from the dose escalation cohort and the first dose expansion cohort, treated with duvelisib BID from day -2 to +28. The primary outcome was safety and tolerability. Secondary outcomes included the incidence and severity of CRS and ICANS, overall response rate (ORR), and progression-free survival (PFS). 17 patients are included in this analysis, including 6 patients in dose escalation and 11 of 14 planned patients in dose expansion cohort A, with full enrollment of cohort A expected prior to presentation. Median age was 68 years (range: 28 - 79) and 53% were male. Diagnoses included DLBCL (n = 13), MCL (2), FL (1) and PBMCL (1). For CAR-T cell therapy, patients received axi-cel (10), liso-cel (4), brexu-cel (2) and tisa-cel (1). 3 patients were enrolled on dose level 1 (15 mg BID) and 3 patients were enrolled on dose level 2 (25 mg BID). No patients experienced a dose-limiting toxicity (DLT) during dose escalation and consequently, 25 mg BID was selected as the recommended dose for expansion. 75 adverse events (AEs) were considered possibly (73) or probably (2) related to duvelisib by study investigators, including 14 severe (grade ≥3) AEs. The most common AEs were blood count abnormalities (41), liver function test abnormalities (12), fatigue (8) and nausea (6). The majority of severe AEs were cytopenias (13) and one patient had grade 3 hypokalemia. 13 patients (77%) had AEs attributed to duvelisib, including 6 patients (35%) with severe AEs. 76% of patients (13/17) experienced CRS at a median of 5 days following cell infusion (range 2 - 9) (Figure 1A). In 71% of patients (12/17), the onset of CRS was after day 3. Most were grade 1 (65%) and no patients experienced severe (grade 3 - 4) CRS. The median duration of CRS was 1 day (range: 1 - 7). ICANS occurred in 41% of patients (7/17) at a median of 7 days (range 4 - 10) and 12% of patients experienced severe (grade 3-4) ICANS. The median duration of ICANS was 5.5 days (range: 4 - 11 days). Toclizumab was given to 65% of patients for treatment of CRS and 53% received steroids for CRS and/or ICANS. All 17 patients were evaluable for disease response. At day +30, the overall response rate (ORR) was 71% (12/17) with 47% achieving complete response (CR) rate. At day +100, the ORR was 64% (9/14) with 50% CR. Best response was CR in 71% of patients and stable disease in 18% of patients. No patients had progressive disease (PD) as best response. CAR T cell expansion by flow cytometry was robust at all dose levels, consistent with prior reports (Figure 1B). With a median follow up of 93 days (range: 28 - 406), 53% of patients were alive and in remission. PD occurred in 6/17 (35%) patients with a median time to progression of 89 days (range: 28 - 182). Three patients enrolled on the study have died. One died from disease progression on day +266. Two died in remission from neutropenic sepsis (day +50) and vaping-induced lung injury (day +144). Data from this ongoing phase I study suggests that duvelisib with SoC CAR T-cell therapy is safe and tolerable. Preliminary data from this study suggest that the addition of duvelisib to CAR T-cell therapy may prevent grade 3-4 CRS and also delay the onset of CRS. Although limited follow-up is available, the depth and duration of response is similar to published data for CAR T-cells in this setting.

A Single Center, 10-Year Experience of CALGB-10403 Regimen in AYA Population with Philadelphia-Chromosome Negative Acute Lymphoblastic Leukemia

INTRODUCTION: The use of pediatric-inspired regimens for the treatment of acute lymphoblastic leukemia (ALL) has now become the standard of care in adolescents and adults (AYA). One such regimen, CALGB 10403, had higher rates of event free survival (EFS) and overall survival (OS) compared with historical controls using adult ALL regimens. It was shown to be feasible and efficacious in fit patients up to the age of 40 (Wendy Stock et al., Blood 2019). In 2012, based on emerging data on the improved efficacy of pediatric-inspired regimens in AYA patients, CALGB 10403 was adopted as the standard-of-care regimen in this population at Karmanos Cancer Institute (KCI), an adult cancer treatment center. Here we report our single center, real world experience of using this regimen in a Philadelphia chromosome negative (Ph-) AYA population, approximately 10 years after its adoption. METHODS: We conducted a retrospective chart review of consecutive AYA (ages 18-39) patients with Ph- ALL treated with CALGB 10403 regimen between January 2012 and June 2023 at KCI. Patients who received alternative regimens due to distance from KCI were excluded. Baseline demographic, clinical and molecular characteristics were noted. High-risk cytogenetics were defined as KMT2A rearrangements, hypodiploidy with a chromosome number ≤43, and complex karyotype. Testing for Ph-like ALL was not available in most patients. Beginning in 2019, clonoSEQ assay was used to test for minimal residual disease (MRD), with MRD negativity defined at a threshold of less than 10 -4. Incidence of adverse effects and treatment related mortality were reported to describe safety. Complete response (CR) rate, OS and PFS were used as efficacy outcomes. Kaplan-Meier curves were used to estimate OS and PFS. RESULTS: A total of 17 Ph- AYA patients were treated at KCI with a median age at diagnosis of 25 years (range 18-34). Males and females had a near equal representation (47% and 53%). The patients were predominantly White (64%). The majority of patients had a good ECOG performance status of 0 or 1 (88%). The diagnosis was B-ALL in 9 (53%) and T-ALL in 8 (47%) patients. High risk cytogenetics were present in 3 (80%) of the evaluable patients. None of the patients had CNS involvement at diagnosis. Baseline laboratory parameters expressed as medians were bone marrow blast percentage 80%, WBC count 9.2 x1000/mm 3, hemoglobin 8.4 g/dL, platelets 109 x1000/mm 3, and LDH 480. The median duration of follow-up was 54 months. 15 (88%) patients had CR with induction, and MRD was negative in 4 (57%) of the 7 evaluable patients. 2 (12%) patients had primary refractory disease. One of the patients with refractory disease underwent further therapy with blinatumomab, inotuzumab, CAR-T and allogeneic stem cell transplantation and is alive at 16 months from diagnosis. Another underwent salvage with hyper-CVAD and allogeneic stem cell transplant, and is currently alive at 88 months from diagnosis. Two additional patients were MRD positive after induction (course I) but subsequently attained MRD negativity. One of these eventually relapsed 7.5 months from diagnosis with a mixed phenotypic (T/myeloid) leukemia and died at 10 months, while the other is currently under treatment. An additional patient with CR1 and unknown MRD status had CNS relapse at 35 months, underwent successful hyper-CVAD, reintroduction of intrathecal chemotherapy and allo-HSCT salvage and is alive at 122 months. The 5-year PFS and OS were 74.5% and 94% respectively and the medians were not reached for both. Noteworthy adverse effects include neutropenic fever (65%), liver function tests (LFT) abnormalities (70%), and neuropathy from vincristine (70%). Peg-asparaginase administration was associated with pancreatitis in 12%, thromboembolism in 30% and hypersensitivity reactions in 24% requiring switching to alternative forms of asparaginase products (erwinia and Rylaze). These toxicities were manageable and there were no treatment-related deaths in our cohort. CONCLUSIONS: The pediatric-inspired regimen CALGB 10403 was safe and efficacious in our AYA Ph- ALL population with no deaths due to treatment and a 5-year overall survival of 94%. Toxicities, especially from peg-asparaginase, should be closely monitored. While most patients will attain durable remission/cure, the minority with refractory or relapsed disease can still be successfully salvaged to achieve long term survival.

Liver Disease and Sickle Cell Disease: Auto-Immune Hepatitis more than a Coincidence; A Systematic Review of the Literature.

In patients with SCD, chronic liver damage is a common manifestation. More than 50% of SCD patients have elevated liver enzymes. Common underlying aetiologies include sickle cell hepatic crisis, viral hepatitis, sickle cell intrahepatic cholestasis and hepatic sequestration in the acute setting, and cholelithiasis and iron overload in the chronic setting. Autoimmune hepatitis (AIH) is a rare disease that appears to occur more commonly in the sickle cell disease (SCD) population than in the general population. There are many schools of thought as to why this is the case, including the phosphatidylserine hypothesis, the heme inflammatory hypothesis, the complement generation hypothesis, and the transfusion alloimmunization hypothesis. Due to the natural history of the two illnesses, SCD is almost always diagnosed first in cases of dual pathology. Symptoms such as jaundice, fatigue, and abdominal pain are common in SCD, as are abnormal liver function tests (LFTs). These abnormalities, attributed to the other more frequent liver involvements in SCD, can lead to delays in AIH diagnosis in this population. Corticosteroids, sometimes with other immunosuppressive agents, such as azathioprine, are the cornerstone of acute AIH treatment. However, corticosteroid use in the SCD population has been shown to carry an increased risk of vaso-occlusive crises, providing a treatment dilemma. The following is a review of AIH in the SCD population, where we explore the pathophysiology behind the association between the two disorders, discuss an approach to investigating abnormal LFTs in SCD, and examine treatment options in this population with co-existing diseases.

Сase report of syphilitic hepatitis

Syphilitic hepatitis is a rare clinical presentation of syphilis and is easily misdiagnosed. However, clinical and histopathologic manifestations of Syphilitic Hepatitis can imitate other infectious and non-infectious diseases, and the diagnosis should be considered in patients with abnormal liver function tests. We present an unusual case of syphilitic hepatitis presenting with jaundice and abdominal bloating after treatment with benzylpenicillin, liver enzymes, and mucocutaneous findings improved.

Discontinuation of Levetiracetam and Valproic Acid Due to Adverse Effects in Early Post-traumatic Seizure Prophylaxis.

Levetiracetam (LEV) and valproic acid (VPA) are two anti-epileptic drugs (AEDs) routinely used for post-traumatic seizure (PTS) prophylaxis at our institution. In our practice, VPA is used for its beneficial effects on behavioral agitation and headaches, but it is also associated with abnormal liver function tests (LFTs). Both medications may be associated with thrombocytopenia. There is less literature comparing the adverse effect profiles and discontinuation rates of LEV and VPA in the context of PTS prophylaxis. We conducted a quality improvement (QI) analysis to determine the safety of LEV and VPA for traumatic brain injury (TBI) patients at our institution. In particular, our QI analysis involved calculating the rates of discontinuation or change of drug regimen due to the adverse effects. Our QI analysis focused on patients treated for TBI at our institution during a six-year period. We recorded the AED usedand if the AED was discontinued or switched due to thrombocytopenia, behavioral agitation, headaches, or elevated LFTs (including elevated aspartate aminotransferase or alanine aminotransferase values). We also recorded the incidence of early PTS, defined as seizures within seven days of the TBI. Our QI analysis included patients with a mean age of approximately 49 years with nearly 75% males. The mean Glasgow Coma Scale (GCS) score was 12.88, with 73.11% of patients having a mild GCS. The three leading injury mechanisms were fall, assault, and motor vehicle collision. The three leading types of TBI were traumatic subarachnoid hemorrhage, subdural hematoma, and cerebral contusion. Among patients with no prior history of seizures, we found an early PTS incidence of 7.28%. For patients administered LEV and VPA, 0.11% (1/898) and 3.85% (4/104)had the medication discontinued or changed because of thrombocytopenia (p < 0.001), respectively. For patients on LEV, 4.01% (36/898) and 1.78% (16/898) had the medication discontinued or changed because of behavioral agitation and headaches, respectively. For patients on VPA, 2.88% (3/104) had the medication discontinued or changed because of hepatotoxicity. In total, 5.90% versus 6.73% (p > 0.5) of patients on LEV and VPA, respectively, had their medication regimens changed due to the adverse effects. The incidence of early PTS in our patients is within the range of what has been reported in the literature. The rate of discontinuation of LEV and VPA on account of adverse events is low in the context of PTS prophylaxis. Both medications had similar overall rates of discontinuation. VPA was discontinued more frequently than LEV due to thrombocytopenia, but discontinuation was not common in either case. LEV is associated with behavioral agitation and headaches, which makes VPA a desirable alternative for patients suffering from these symptoms.

The fluorescence imaging for laparoscopic and laparotomic endometrial sentinel lymph node biopsy (FILLES) trial: Siriraj gynecologic sentinel node of endometrial cancer (SiGN-En) study.

The objective of this study is to establish the detection rate of sentinel lymph node (SLN) biopsies and to determine the sensitivity and false-negative rate of SLN biopsies compared with those of systematic pelvic and para-aortic lymphadenectomies in endometrial cancer. This prospective cohort study enrolled patients with endometrial cancer who were scheduled for surgical staging. Patients with a history of chemotherapy or radiotherapy, an abnormal liver function test, or an allergy to indocyanine green (ICG) were excluded. All patients underwent surgical staging with an ICG injection at the cervix. SLNs were identified by a near-infrared fluorescent camera. All SLNs were sent to a pathologist for ultrastaging. From November 2019 to June 2023, 142 patients underwent SLN mapping and surgical staging. SLNs were not detected bilaterally in 8 patients. The detection rate of the SLN biopsies in this study was 91.2%. Thus, the accuracy of the SLN biopsies was 97.6%. The sensitivity for finding metastatic SLNs was 84.2%, with a negative predictive value of 97.22%. A SLN biopsy in endometrial cancer has a high detection rate and high accuracy. However, surgical expertise and a learning curve are required.

Analysis of Liver Function Test in Common Bile Duct Stone: A Descriptive Cross sectional study

Introduction: Liver function test (LFT) is a useful tool to differentiate between the obstructive and hepatocellular cause for biliary obstruction. Therefore this study was done to see the accuracy of LFT in predicting common bile duct (CBD) stones. Methods: A descriptive cross sectional study was carried out on patient undergoing endoscopic retrograde cholangiopancreatography for CBD stones at Bharatpur Hospital and Dev Hospital from 2021 June 15 to 2022 October 15. Ethical clearance was taken from Institutional Review Committee Bharatpur Hospital reference number 079/80-013. The convenient sampling method was applied. Data were collected and analyzed in statistical package for the social sciences version 22. Results: Out of 95 patients higher aged female predominance was seen. The overall incidence of abnormal LFT in CBD stones was 85.3%. All the parameters of LFT were raised in majority of the cases of CBD stones and among these, SGOT was mostly increased (75.6%). In patients with ERCP findings of sludge in bile duct have increased total, direct and indirect bilirubin than in patient with CBD stone and this finding was found to be statistically significant. However, other liver parameters were comparable.Similarly, total, direct and indirect bilirubin, serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT) and alkaline phosphatase (ALP) were equally raised with both group of CBD stones with and without cholecystitis. Conclusion: Liver function test was equally raised in both case of CBD stone with and without cholecystitis. Although ALP and total bilirubin represented the most reliable predictors in obstructive jaundice, SGOT might also be added tool to exclude choledocholithiasis.