Elevated Liver Enzymes Research Articles

A likely pathogenic homozygous frameshift variant in BLOC1S6 associated with a rare form of congenital Hermansky-Pudlak syndrome 9

Hermansky-Pudlak syndrome (HPS) is a collection of autosomal recessive multisystemic disorders with at least 11 different types, categorized on the basis of involved genes. The disease is mostly characterized by tyrosinase-positive oculocutaneous albinism (OCA), platelet storage deficiency, absence of platelet dense bodies, and immune deficiency. Here we described a 2-month-old female infant with generalized hypotonia, recurrent infections, bilateral optic atrophy, nystagmus, cerebral atrophy, and elevated liver enzymes. Unlike her parents, she had chestnut colored hair, fair skin, and brown eyes. Parents had a consanguineous marriage, and their first child had died with similar symptoms at the age of 5 months. Whole exome sequencing (WES) was performed on DNA extracted from the patient's peripheral blood. Following the bioinformatics analysis, a likely pathogenic novel variant in the fifth exon of the BLOC1S6 gene (NM_001311255: c.506dupT: p. L169Ffs*33) was introduced by the Sadra Medical Genetic Laboratory. This variant was confirmed in the patient and segregated in both parents by Sanger sequencing.This report presented the first congenital case of HPS-9 worldwide that might have led to early neonatal death. Our current patient shows new considerable features related to the BLOC1S6 gene variant and HPS-9, which is a valuable source for future research, prediction, clinical management, genetic counseling, and prenatal diagnosing.

Hepatoprotective and neuroprotective effects of quinacrine against bile duct ligation-induced hepatic encephalopathy in rats: Role of bone morphogenetic proteins signaling

AimsThis study aimed to assess the potential protective effect of quinacrine, an FDA approved antimalarial drug with reported anti-inflammatory effects, on hepatic encephalopathy (HE) in a bile duct ligation (BDL) experimental model and to investigate the mechanisms responsible for this effect, namely those associated with the liver-brain axis, particularly, bone morphogenetic protein 2 (BMP2) signaling. Materials and methodsFive groups of rats were selected at random: sham, BDL, (BDL+ quinacrine 5), (BDL+ quinacrine 10), and (quinacrine 10 + sham). Daily Intraperitoneal (I.P.) administration of quinacrine was initiated on the surgery day and continued for 28 days. Key findingsResults showed that rats that underwent BDL exhibited marked elevation of serum liver enzymes, ammonia, total bilirubin, together with oxidative stress, inflammation, dysregulated farnesoid x receptor (FXR), dysregulated BMP2 signaling and escalated fibrotic markers indicating hepatotoxicity, cholestasis and fibrosis. Besides, neurotoxicity was detected as manifested by cognitive deficits and dysregulation of hippocampal FXR, BMP2 signaling, WNT3A signaling, brain derived neurotrophic factor (BDNF), phospholipase A2 (PLA2) and glial fibrillary acidic protein (GFAP). In contrast, co-treatment with quinacrine mitigated BDL-induced hepatotoxicity, cholestasis, fibrosis, and neurotoxicity. Notably, quinacrine improved learning and memory and restored FXR, BMP2 signaling in the liver and hippocampus. In addition, quinacrine restored hippocampal WNT3A signaling, BDNF, whereas it downregulated expression of hippocampal PLA2 and GFAP. SignificanceThese findings demonstrated implication of BMP2 signaling in the molecular process of BDL-induced HE and proposed that quinacrine has potential hepatoprotective and neuroprotective properties against HE.

The Impact of Methamphetamine on Liver Injury in Iraqi Male Addicts

Methamphetamine (METH) is a powerful stimulant that affects neurochemical processes controlling heart rate, appetite, blood pressure, body temperature, and wakefulness, making it highly susceptible to abuse. Liver enzymes such as ALT, AST, ALP, and GGT are crucial for liver function. Albumin, a protein synthesized by healthy liver cells, serves as an indicator of chronic liver disease. Additionally, hepatocytes produce bile acids, which are essential for the secretion of bile salts into the bile canaliculi. Disruption in this secretion results in the accumulation of bile salts in the canaliculi, leading to intrahepatic cholestasis. METH-induced liver toxicity involves disruptions in hepatic metabolism, oxidative stress, and increased body temperature, affecting cellular processes such as cell division and the cell cycle and potentially accelerating liver cell apoptosis. The study explores the link between liver toxicity and hepatocyte damage in Iraqi males suffering from addiction. This is a case-control study, conducted at Ibn-Rushed Psychiatric Hospital in Baghdad from July 2023 to February 2024, involved 196 males, with addiction durations exceeding 24 months with varying degrees of methamphetamine (METH) addiction. The study included 187 healthy male controls with no history of drug addiction. Participants were aged 18 to 40 years. Diagnosis was confirmed using a drug test screening card administered by a specialist. The study included liver function tests (ALT, AST, ALP, and GGT), total bilirubin, and albumin concentration assessments. Significant differences were observed between the addicts and controls, particularly a marked decrease in serum albumin concentration in the addicted males. The ROC curve classification model at various thresholds demonstrated that liver enzymes, especially ALT, ALP, and GGT, exhibited increased sensitivity to METH addiction. A histopathological examination was conducted on a deceased 38-year-old male who had a six-year history of chronic amphetamine addiction to confirm liver injury and the resulting elevation of liver enzymes. The findings of this study indicate that METH greatly affects liver function, suggested to the importance of following a preventative measures and effective treatment approaches for monitoring METH addiction progress.

Pregnancy-related acute kidney injury leads to hypertension, reduced kidney function and cognitive impairment in postpartum rats

IntroductionWomen with hypertensive disorders of pregnancy such as HELLP (hemolysis, elevated liver enzyme, low platelet) Syndrome are affected by acute kidney injury during pregnancy (PR-AKI) at higher rates than women without hypertension. Both hypertensive disorders of pregnancy and Acute Kidney Injury (AKI) outside the context of pregnancy have been associated with an increased risk of developing Chronic Kidney Disease (CKD) and cognitive impairment. In our current study, we set out to determine if PR-AKI led to the development of CKD and impaired cognition in the postpartum period and if HELLP syndrome exacerbates the impairments.MethodsUsing timed-pregnant Sprague Dawley rats, on gestational day (GD) 12, mini-osmotic pumps infusing anti-angiogenic factors were surgically placed in the intraperitoneal cavity to induce HELLP. On GD18, AKI was induced via bilateral renal reperfusion ischemia surgery. Mean arterial pressure and birth outcomes were used to assess the global effects of AKI, and liver enzymes were used to assess HELLP. CKD was assessed by measuring glomerular filtration rate (GFR), urinary output, and renal fibrosis. Anxiety-like behaviors, object recognition memory, spatial memory, and avoidance memory were assessed via behavioral experiments.ResultsHELLP + AKI rats demonstrated more evidence of renal injury, hypertension, and behavioral deficits compared to normal pregnant animals. In addition, AKI had a negative impact on birth outcomes and maternal survival.ConclusionHELLP + AKI together led to evidence of persistent hypertension, progressive renal dysfunction, and cognitive impairment, which were exacerbated compared to AKI or HELLP alone. These findings suggest that PR-AKI in the presence of a hypertensive disorder of pregnancy, such as HELLP, leads to the development of CKD, cognitive dysfunction, and hypertension.

Preparation of gallic acid-loaded chitosan nanoparticles and their chemoprotective effects on N-ethyl-N-nitrosourea-induced hepatotoxicity and mortality in rats.

N-ethyl-N-nitrosourea (ENU) as n-nitrosamine and alkylating agent, ubiquitous within living cells and in the environment can act as a full carcinogen and induce tumor formation in various tissues such as liver. In this study, gallic acid-loaded chitosan nanoparticles (GANPs) were synthesized and evaluated for their chemopreventive effect against ENU-induced hepatotoxicity and mortality in rats. Twenty-four male Wistar rats were divided into four groups including: control, ENU (single doses of 50mg/kg via intraperitoneal injection), GA + ENU and GANPs + ENU. Animals were orally pretreated with GA (50 mg/kg) and GANPs (50 mg/kg) for 30 days, and liver injuries induced by ENU on the 31st day of study. After ENU administration, weight changes and mortality were monitored during 30 days, and then the animals were sacrificed and alpha-fetoprotein (AFP) as a tumor marker, liver function tests (ALT, AST and ALP), oxidative stress markers (GSH and MDA), mitochondrial toxicity parameters, and histopathological assessment were evaluated. Except for AFP and MDA, ENU caused significant elevation of liver enzymes, mitochondrial ROS formation, collapse of mitochondrial membrane potential depletion of GSH, histopathological abnormalities and mortality in rats. Our data showed that GANPs significantly increased the survival of rats by up to 66%, delayed in death time and prevented weight changes after exposure to ENU. Moreover, GANPs restored liver enzyme levels, ROS formation, mitochondrial dysfunction, GSH levels, and histopathological abnormalities towards normal. Our findings suggest that GANPs revealed a significant protective effect against deadly toxicity induced by ENU as an alkylating full carcinogen agent in liver tissue.

Atypical Presentation of Subcapsular Liver Hematoma With a Delayed Onset of Hemolysis, Elevated Liver Enzymes, Low Platelet Count (HELLP) Syndrome

Atypical Presentation of Subcapsular Liver Hematoma With a Delayed Onset of Hemolysis, Elevated Liver Enzymes, Low Platelet Count (HELLP) Syndrome

Human papillomavirus infections during pregnancy and adverse pregnancy outcomes: a Scandinavian prospective mother-child cohort study.

Human papillomaviruses are common in the urogenital tract amongst women of childbearing age. A few studies indicate a possible association between human papillomavirus infections in pregnancy and adverse pregnancy outcomes whilst other studies find no such association. We aimed to investigate the association between human papillomavirus infections during pregnancy and adverse pregnancy outcomes linked to placental dysfunction, including hypertensive disorders of pregnancy, gestational diabetes mellitus and newborns small for gestational age. Pregnant women from the general population in Norway and Sweden were enrolled at the time of routine mid-gestational ultrasound examination. Urine samples collected at mid-gestation in 950 and at delivery in 753 participants, were analyzed for 28 human papillomavirus genotypes, including 12 high-risk genotypes. Participants completed electronic questionnaires at enrollment and medical records were reviewed for background characteristics and for the following adverse pregnancy outcomes: hypertensive disorders of pregnancy including gestational hypertension, preeclampsia, superimposed preeclampsia, eclampsia and Hemolysis Elevated Liver enzymes and Low Platelets (HELLP) syndrome, gestational diabetes mellitus, and newborns small for gestational age. Associations between adverse pregnancy outcomes and (a) any human papillomavirus, high-risk human papillomavirus and human papillomavirus genotype 16 infection at mid-gestation, (b) multiple genotype infections at mid-gestation, and (c) persisting infections during pregnancy were assessed with univariable and multivariable logistic regression models. Missing covariates were imputed using multiple imputation. At mid-gestation, 40% (377/950) of women were positive for any of the 28 genotypes, 24% (231/950) for high-risk genotypes and human papillomavirus 16 was found in 6% (59/950) of the women. Hypertensive disorders of pregnancy was observed in 9% (83/950), gestational diabetes mellitus in 4% (40/950) and newborns small for gestational age in 7% (67/950). Human papillomavirus infection with any genotype, high-risk or human papillomavirus genotype 16 at mid-gestation was not associated with adverse pregnancy outcomes. No associations were found for multiple genotype infections at mid-gestation or persisting infections. In a general population of pregnant women, we found no evidence of human papillomavirus infections during pregnancy being associated with hypertensive disorders of pregnancy, gestational diabetes mellitus, or newborns small for gestational age. Trial registration The study is registered at ClincialTrials.gov; NCT02449850 on May 19th, 2015.

Gentamicin Induced Damage in Nephrotoxicity and Hepatotoxicity in Male Rabbits: The Protective Effect of Cinnamon

One common aminoglycoside antibiotic that is well-known for its ability to treat gram-negative bacterial infections is gentamicin. Its nephrotoxic and hepatotoxic side effects, which are mostly brought about by the production of free radicals that harm kidney and liver cells, frequently restrict its therapeutic application. On the other hand, strong antioxidants found in cinnamon, a popular spice and therapeutic plant, have been demonstrated to have protective properties against oxidative stress. In order to assess the protective role of cinnamon, the current study examines how cinnamon affects gentamicin-induced changes in biochemical markers, liver enzymes in male rabbits. Treatment groups included a control group, a gentamicin-only (GIN) group, a cinnamon-only (CIN) group, and a combined cinnamon-gentamicin (CIN+GIN) group. The results showed that GIN group elevated liver enzymes, specifically aspartate transaminase (AST) and alanine transaminase (ALT), suggesting possible hepatotoxicity. The dose of cinnamon decreased these enzyme levels, while the combination therapy kept the AST levels close to control. Biochemical examination revealed that cinnamon reduced these alterations, particularly in the combination therapy group, while gentamicin increased total protein, urea, and creatinine levels, indicating renal and hepatic stress. The study concludes by highlighting the potential of cinnamon in reducing gentamicin-induced toxicity, specifically through its effects on lipid profiles, liver enzyme activities, body weight, blood profiles, and biochemical markers. This suggests that cinnamon could be used as an adjuvant therapy to reduce the negative effects of gentamicin".

Transient Elevation of Liver Function Tests and Bilirubin Levels After Laparoscopic Cholecystectomy.

Background and Objectives: Laparoscopic cholecystectomy constitutes the current "gold standard" treatment of symptomatic gallstone disease. In order to avoid intraoperative vasculobiliary injuries, it is mandatory to establish the "critical view of safety". In cases of poor identification of the cystic duct and artery leading to a missed intraoperative injury, patients present with elevated liver function tests (LFTs) or increased bilirubin postoperatively. The aim of this study is to present a series of patients of our institute with elevated liver enzymes and bilirubin after laparoscopic cholecystectomy in the absence of intraoperative injury or any other obvious etiology and to provide a possible explanation of this finding. Materials and Methods: From 2019 to 2023, 200 patients underwent elective laparoscopic cholecystectomy at the Papageorgiou General Hospital and at the European Interbalkan Medical Center of Thessaloniki utilizing the "critical view of safety" method. We retrospectively collected the intraoperative reports, and the pre- and postoperative imaging and laboratory studies of the patients included in this series. Postoperative LFTs and bilirubin levels were extracted and the reason for their transient elevation was examined. Results: From 200 cases of laparoscopic cholecystectomy, elevated LFTs and bilirubin were found in six patients on the first postoperative day, which is suggestive of a missed intraoperative injury. All patients were asymptomatic. During the investigatory workup, a triple-phase CT of the liver and/or an MRCP were ordered, but no pathological findings, such as biliary injury, hepatic artery injury or choledocholithiasis, were found. On postoperative day 3, LFTs and bilirubin levels decreased or normalized without any intervention. No postoperative complications were reported. Conclusions: In select cases, a transient increase in LFTs and/or bilirubin may be observed in the early postoperative period after elective laparoscopic cholecystectomy in the absence of an obvious etiology. A possible interpretation of these findings could involve the pneumoperitoneum or the anesthesia regimens used intra- or perioperatively. The specific cause, however, remains undetermined and yet to be examined by future studies.

Genetic, Clinical, and Biochemical Characterization ofa Large Cohort of Palestinian Patients With Fanconi-Bickel Syndrome.

This study aims to investigate the clinical, biochemical, and genetic characteristics of Fanconi-Bickel syndrome (FBS) in a cohort of 20 individuals from Palestine and to identify novel pathogenic variants. A retrospective analysis was conducted on medical records from Al-Makassed Hospital's pediatric department spanning 2015 to 2023. Individuals diagnosed with FBS via molecular genetic testing were included in the study. Among the 20 genetically confirmed FBS patients, hepatomegaly was prevalent in 95%, whereas 70% exhibited both developmental delay and hypophosphatemic rickets, and 68.4% experienced growth retardation. Hypertriglyceridemia (HTG) was universal. Elevated liver enzymes and alkaline phosphatase were common, along with hypophosphatemia (95%) and urinary abnormalities. Genetic analysis revealed five distinct SLC2A2 pathogenic variants, including three previously unreported variants: p.Gln23Arg (c.68A > G), p.Thr353Arg (c.1058_1059delinsGG), and an exon 7 deletion. This study presents the largest single-center cohort of FBS patients, expanding our understanding of the disorder's phenotypic and genotypic spectrum. Despite FBS generally carrying a favorable prognosis, timely diagnosis remains crucial to prevent severe complications.

CRISPR-Cas9 Gene Editing with Nexiguran Ziclumeran for ATTR Cardiomyopathy.

Transthyretin amyloidosis with cardiomyopathy (ATTR-CM) is a progressive, often fatal disease. Nexiguran ziclumeran (nex-z) is an investigational therapy based on CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease) targeting the gene encoding transthyretin (TTR). In this phase 1, open-label trial, we administered a single intravenous infusion of nex-z to patients with ATTR-CM. Primary objectives included assessment of the effect of nex-z on safety and pharmacodynamics, including the serum TTR level. Secondary end points included changes in N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, high-sensitivity cardiac troponin T levels, the 6-minute walk distance, and the New York Heart Association (NYHA) class. A total of 36 patients received nex-z and completed at least 12 months of follow-up. Of these patients, 50% were in NYHA class III and 31% had variant ATTR-CM. The mean percent change from baseline in the serum TTR level was -89% (95% confidence interval [CI], -92 to -87) at 28 days and -90% (95% CI, -93 to -87) at 12 months. Adverse events were reported in 34 patients. Five had transient infusion-related reactions, and two had transient liver-enzyme elevations that were assessed as treatment-related. Serious adverse events, most of which were consistent with ATTR-CM, were reported in 14 patients. The geometric mean factor change from baseline to month 12 was 1.02 (95% CI, 0.88 to 1.17) in the NT-proBNP level and 0.95 (95% CI, 0.89 to 1.01) in the high-sensitivity cardiac troponin T level. The median change from baseline to month 12 in the 6-minute walk distance was 5 m (interquartile range, -33 to 49). A total of 92% of the patients had either improvement or no change in their NYHA class. In this phase 1 study involving patients with ATTR-CM, treatment with a single dose of nex-z was associated with transient infusion-related reactions and consistent, rapid, and durable reductions in serum TTR levels. (Funded by Intellia Therapeutics and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT04601051.).

Lactate dehydrogenase as a biochemical marker for prediction of maternal and perinatal outcomes in hypertensive disorders in pregnancy

Hypertensive disorder of pregnancy includes new onset hypertension in pregnancy that is gestational hypertension and already existing hypertension that is chronic hypertension and gestational hypertension sometimes worsened by preeclampsia. Preeclampsia can cause complications such as eclampsia, HELLP syndrome, renal failure, pulmonary edema, stroke, and left ventricular failure. We aim to assessthe predictive role ofLactate Dehydrogenase value in Hypertensive disorders in pregnancy.After obtaining the informed consent, pregnant patients who were visiting Tertiary care centre and who were more than 28 weeks period of gestation were enrolled. Patients from both antenatal OPD clinics and from those who were presenting in emergency were included in this study. Serum levels of LDH were tested. Patients were monitored till delivery and 6 weeks following childbirth.The Mean serum levels of lactate dehydrogenase (LDH) in eclamptic group was 1495.000±859.1230, 804.569±224.5519 in severely preeclamptic group and in mild preeclamptic group ,mean LDH levels were 520.062±110.3944. The difference between both the groups was statistically significant (p < 0.001).Women with serum LDH levels > 800 IU/L and LDH levels between 601-800 IU/L, experienced considerably greater complications in preeclamptic-eclamptic group as compared to those with serum LDH levels < 600 IU/L.Thepreeclamptic-eclamptic group of women had increased serum LDH levels. Greater LDH levels were linked to worse outcomes for mothers including placental abruption, hemolysis elevated liver enzymes low platelet count (HELLP syndrome), pulmonary edema and maternal death and they were also linked to fetal complications including intrauterine fetal death (IUFD), intrauterine growth restriction and neonatal intensive care unit (NICU) admission.

Ultrasound evaluation of kidney and liver involvement in Bardet–Biedl syndrome

BackgroundBardet–Biedl syndrome (BBS) is a rare autosomal-recessive ciliopathy with pathogenic variants in 26 BBS genes. It affects multiple organs, including the kidney and liver, with varying degrees regarding extent and time of first manifestation. Structural renal anomalies are an early feature and end-stage kidney disease (ESKD) cumulates to 25% in adulthood. Early-onset hyperphagia-associated obesity is another major symptom and contributes to liver pathology, presenting as steatosis/fibrosis. Aim of this study is the evaluation of high-end ultrasound (US) technologies in BBS patients regarding their potential to discriminate liver and kidney tissue pathology at an early stage.Materials and methodsPatients with genetically proven BBS were recruited from the University Children’s Hospital of Essen and from BBS patient days hosted in Germany. Acute illness was an exclusion criterion. Clinical and laboratory data were extracted from patients’ digital records or medical letters. High-resolution ultrasound (US) imaging was utilized, including attenuation imaging (ATI), shear wave elastography (SWE) and dispersion (SWD) of liver tissue.Results49 BBS patients (24/49 male; 1.1–51.0 years, mean 17.8 years) were included in the study. Mean body weight (SDS 2.13 ± 1.33) and BMI (SDS 2.64 ± 1.18) were increased. Structural kidney abnormalities (dysplasia, cysts) were present in 75% (36/48), and persistent fetal lobulation in 44% (21/48). Renal function was impaired in 27% (13/49) of whom 3 had ESKD (kidney transplantation (n = 2), hemodialysis (n = 1)). Elevation of liver enzymes was detected in 38% (16/42). In 51% (25/49) ATI of liver tissue was increased, indicating hepatic steatosis, and correlated with BMI SDS, liver size, and enzymes. SWE was elevated in 61% (30/49), suggesting hepatic fibrosis, and it correlated with BMI and GGT. Patients with pathogenic variants in BBS10 showed a tendency towards higher ATI, reduced GFR, and higher BMI SDS.ConclusionsWe detected kidney and liver abnormalities in a higher percentage of BBS patients than previously reported, indicating a high sensitivity and diagnostic yield of the evaluated high-end US applications. ATI detected liver pathology early (partially prior to liver enzymes) and revealed differences related to the affected genes. Evidence of tissue pathology at an early stage may improve diagnostics and the evaluation of therapeutic approaches.

German Real-World Experience of Patients with Diverse Features of Acute Intermittent Porphyria Treated with Givosiran.

Background/Objectives: Acute intermittent porphyria (AIP) is a metabolic disease characterised by neurovisceral crises with episodes of acute abdominal pain alongside life-altering, and often hidden, chronic symptoms. The elimination of precipitating factors, hemin therapy, and pain relief are strategies used to treat porphyria symptoms, but are often reserved for patients suffering recurrent, acute attacks. Givosiran (siRNA) is an emerging AIP therapy capable of silencing delta-aminolevulinic acid synthase-1 (ALAS1) and, in turn, reducing the accumulation of delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) that precede porphyria symptoms. The aim of this study was to investigate the efficacy and safety of givosiran administration in patients with both acute and chronic AIP burden, who were poorly responsive to current therapies, using a personalised medicine approach. Methods: Real-world data were collected in consecutive patients treated with givosiran at an accredited German Porphyria Clinical Center. Biochemical, clinical, and HR-QoL outcomes were monitored alongside adverse events (AEs). Results: Twenty-eight patients treated between 2018 and 2024 were sub-categorised into groups corresponding to Ipnet terms 13 'Sporadic Attacks, 5 'Symptomatic High Excretors', 5 'Prophylactic Heme', and 5 "Recurrent Attacks'. The mean time from diagnosis to treatment was 9.2 years (range in months 1-324), and the mean duration of treatment was 30 months (range 3-68). After 6 months of monthly givosiran injection (2.5 mg/kg), all patients' ALA levels reached <2ULN, and 60% of patients attained PBG levels < 2ULN (p < 0.001). These biochemical responses were not different between sub-groups (p > 0.05). Clinically, 75% of patients' chronic and acute porphyria symptoms improved. The total patient populations' annualised attack ratio (AAR) improved; Historical AAR: 2.9 (0-12.0) vs. Givo AAR: 0.45 (0-3.0) (p < 0.01). During follow-up, nine patients experienced minor breakthrough episodes. Of these, three patients required hemin infusion. An association between clinical success and a shorter interim period between diagnosis and treatment was evident (r = -0.522, p = 0.0061). All patients' indices of HR-QoL improved under givosiran, including mental health (38%, p < 0.0001) and pain (38%, p < 0.0001). Patient-reported health (givosiran 77.9% vs. baseline 37.1%, p < 0.0001) and clinical outcome scores (86.9%: good-very good) were also positive. Two patients withdrew from treatment <6 months, citing fatigue, which was a common side effect. A mild elevation in liver enzymes (AST and/or ALT < 1.5ULN, 15.4%) and reduced glomerular filtration rates (GFR, 11.5%) were also evident, but no life-threatening adverse events (AEs) were attributed to givosiran treatment. Conclusions: Givosiran is effective in preventing severe acute attacks and reducing the chronic health burden in patients with acute intermittent porphyria. Importantly, HR-QoL improved in patients suffering chronic AIP burden with few incidences of historical attacks. All patients experienced substantially improved mental health, ease of living, and self-perceived health.

CTNI-56. PHASE I STUDY OF VORINOSTAT AND TEMSIROLIMUS IN NEWLY DIAGNOSED OR PROGRESSIVE DIFFUSE INTRINSIC PONTINE GLIOMA

Abstract BACKGROUND Diffuse intrinsic pontine glioma (DIPG) carries a poor prognosis with a median survival of less than 12 months. Histone mutation, K27M, and AKT pathway dysregulation play key roles in tumorigenesis. There is no curative treatment with radiation therapy, which currently remains the standard treatment. METHODS This is a phase I study of vorinostat and temsirolimus in newly diagnosed (stratum 1) and progressive (stratum 2) DIPG. The primary aims are to determine the safety, maximum tolerated dose, and toxicities (NCT02420613). Stratum 1 received radiation concurrently with vorinostat, followed by vorinostat and temsirolimus for up to 10 cycles. Stratum 2 received vorinostat and temsirolimus for up to 12 cycles. In stratum 1, vorinostat was administered daily at 230 mg/m2. The maintenance phase (both strata) included concurrent vorinostat 230 mg/m2 daily and temsirolimus 25 or 35 mg/m2 (Days 1 and 8). RESULTS Six patients were enrolled, three in each stratum. Three of the six patients had confirmed H3 K27M mutations. No dose-limiting toxicity was observed, and most adverse effects were limited to grades 1 or 2, including fatigue, nausea, vomiting, myelosuppression, hyperlipidemia, hyperglycemia, elevated liver enzymes, and creatinine. However, one patient experienced grade 3 leukopenia. Two of the three patients in stratum 1 showed evidence of radiographic response after the chemoradiation phase, of whom one patient had progression-free survival of 12 months and completed the 10 maintenance cycles. All patients at stratum 2 had disease progression with no radiographic response. CONCLUSION Overall, the combination of temsirolimus and vorinostat is well tolerated and safe, prompting the need for larger studies to investigate its efficacy. Due to the small number of patients, the study’s findings are limited, and trends in efficacy should be interpreted with caution.

QOL-29. PREVALENCE, MANAGEMENT, AND OUTCOMES OF PROCARBAZINE-ASSOCIATED HYPERSENSITIVITY REACTIONS IN PATIENTS RECEIVING PCV FOR LOW-GRADE GLIOMA

Abstract Procarbazine is an alkylating agent commonly used to treat low-grade gliomas as part of the PCV regimen. The use of procarbazine is frequently limited by the development of hypersensitivity reactions (HSRs), which often require dose reduction or cessation of procarbazine therapy prior to the completion of a planned treatment course. The prevalence, clinical characteristics, and potential predictors of these reactions are not well defined. We conducted a retrospective cohort study of patients with low-grade glioma who received PCV between January 2016 and January 2024 at a tertiary academic hospital. Data on patient demographics, tumor type, clinical characteristics, treatment course, and hypersensitivity reactions were collected and analyzed. 61 total patients were included. The overall prevalence of HSRs was 60.7% (95% CI: 48.4% - 72.9%). The median cycle during which HSRs occurred was cycle 3 (IQR: 2-4, Range: 1-5). All HSRs involved the development of rash, with 86.5% being pruritic and 21.6% involving the face. Treatments for HSRs included antihistamines (62.2%), topical corticosteroids (35.1%), and systemic corticosteroids (27.0%). Three patients with HSRs presented to the emergency department with concern for anaphylaxis, and one required treatment with epinephrine. Out of six patients rechallenged with procarbazine after experiencing HSRs, one patient redeveloped a diffuse, pruritic rash that resolved with systemic corticosteroids. A multiple logistic regression analysis was performed to assess the association between HSRs and gender, age at PCV C1D1, elevated liver enzymes, and concomitant anticonvulsant use, but no significant correlation was observed. In summary, our study provides a contemporary and comprehensive analysis of the prevalence and severity of HSRs to procarbazine in patients with low-grade glioma. The high rate of HSRs in this population, including a relatively high rate of suspected anaphylaxis, should be considered carefully by clinicians in choosing chemotherapy for low-grade glioma and warrants routine counseling and close monitoring.

Diagnostic dilemma: a collision of pancreatic neuroendocrine tumor G3 and adenocarcinoma with extensive fibrosis.

An 82-year-old man presented with intermittent abdominal pain and elevated liver enzymes. Blood tests showed normal levels of tumor markers (CEA, CA19-9, NSE). Contrast-enhanced computed tomography (CE-CT) revealed a 20mm hypovascular mass in the pancreatic head. Magnetic resonance imaging indicated low intensity on both T1- and T2-weighted images and high intensity on diffusion-weighted images. Endoscopic ultrasonography visualized an irregular hypoechoic mass. Initially, it was diagnosed as pancreatic ductal adenocarcinoma (PDAC) based on imaging. Subsequent histopathological analysis via endoscopic ultrasound-guided fine-needle aspiration revealed a neuroendocrine tumor (NET). The preoperative diagnosis was changed to a pancreatic NET grade1. Consequently, a pancreaticoduodenectomy was performed. Histopathological examination of the resected specimen unveiled a mixed tumor-NET-Grade1/Grade3 and invasive PDAC. No clear transition between the NETs and PDAC was observed. The high grade of NET with significant fibrosis contributed to decreased enhancement of CE-CT. Finally, we diagnosed this case as a pancreatic collision tumor involving both NET and PDAC components, with lymph node metastases attributed to the NET components. In this case, achieving an accurate preoperative diagnosis was challenging despite utilizing both imaging and biopsy diagnostics. This unique case underscores the difficulties encountered in the preoperative assessment of mixed tumors.

The effect of hereditary thrombophilia on recurrent pregnancy loss: a retrospective cohort study

ObjectiveThrombophilia screening has been performed in patients with conditions such as previous fetal death, (fetal growth restriction) FGR, preeclampsia, (hemolysis. elevated liver enzyme, low platelet count) HELLP Syndrome, previous abruptio placentae, previous thrombosis in pregnancy, and abnormal placental histology. The actual role of hereditary thrombophilia in recurrent pregnancy loss (RPL) is still debated. This study was intended to determine the incidence of specific gene defects for hereditary thrombophilia and to ascertain their impact on RPL in central Anatolia in Turkey.MethodsThis retrospective cohort study was performed between January 2012 and December 2022. All pregnant women with a complete hereditary screening profile were included. The investigated gene polymorphisms were methylenetetrahydrofolate reductase (MTHFR) C677T, MTHFR A1298C, Factor V Leiden G1691A, and Factor II prothrombin G20210A. Cases of pregnant women at least two or more consecutive pregnancy losses before 22 weeks of gestation were defined as RPL. The rates of genetic screening and their association with RPL were analyzed.ResultsRPL was identified in 224 (27.58%) of the 812 pregnant women with complete genetic screening. Although there was no difference in terms of age, body mass index, numbers of ectopic pregnancies, molar pregnancies, or dilatation & curettage (p > 0.05), gravity (2.0 [2.0–3.0] vs. 4.0 [3.0–5.0]), parity (1.0 [1.0–2.0] vs. 1.0 [0–1.0]), live birth (1.0 [1.0–2.0] vs. 1.0 [0–1.0]), anembryonic pregnancy (0 [0–0] vs. 0 [0–0]), miscarriage (0 [0–1.0] vs. 3.0 [2.0–3.0]), and stillbirth (0 [0–0] vs. 0 [0–0]) numbers differed significantly between the groups (p < 0.05). While no significant differences were determined in MTHFR A1298C, Factor V Leiden, factor II prothrombin G20210A, or homocysteine levels (p > 0.05), the homozygous MTHFR C677T positivity rates differed significantly (6.3% in the non-RPL group vs. 11.6% in the RPL group, p = 0.027) .ConclusionThe homozygous MTHFR C677T polymorphisms was found to be more frequent in women with RPL. Further studies with larger cohorts are needed to confirm our results.

HELLP Syndrome Developing at 14 Weeks of Gestation: An Extremely Rare Case Report and a Literature Review

Introduction: Hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome is a disease of pregnancy that occurs very rarely before 20 weeks of gestation. We report a case of HELLP syndrome developing at 14 weeks and 2 days of gestation. Case Presentation: A 33-year-old Asian primipara at 14 weeks and 2 days of gestation visited the emergency room with a fever and headache. Initial blood pressure was 140/70 mm Hg, temperature 38.5°C, heart rate 130 beats/min with tachycardia. Her prenatal examination has been unremarkable, and fetal ultrasonography was within normal range. The laboratory results showed low platelet count with elevated liver enzymes, D-dimer, and fibrinogen but no sign of jaundice. Her WBC differential suggested a bacterial infection. Thus, we diagnosed early HELLP syndrome and immediately started conservative treatments. One day after admission, symptoms and laboratory results showed aggravation of the disease. We performed termination, followed by dilation and curettage for retained placenta. Her general condition improved rapidly after the operation. Placental biopsy showed both acute and chronic inflammation. She also had anticardiolipin antibody IgM, and after discharge, she was referred to a rheumatology specialist to address the antiphospholipid syndrome issue. Discussion: Although the triggers of HELLP syndrome are unclear, a recent inflammatory hypothesis suggests that placenta-derived inflammatory cytokines are involved. In our case, the anti-cardiolipin antibody may have triggered microangiopathy of the placenta. Our analysis of published HELLP cases revealed that, apart from the three diagnostic criteria, the most common abnormal laboratory finding was antiphospholipid antibodies. Therefore, despite its rarity, if a sign of inflammation is present in a patient, it is important to consider HELLP syndrome regardless of gestational age

Rescue of a spontaneous subcapsular hepatic hematoma associated with HELLP syndrome: A case report.

Spontaneous subcapsular hepatic hematoma (SSHH) is a rare yet severe complication of hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome that can lead to life-threatening situations for both the mother and fetus. Determining an appropriate therapeutic strategy remains challenging, as it involves choosing between surgery, microinvasive percutaneous transhepatic drainage, or conservative treatment alone. Further successful cases are needed to support the optimal option. We retrospectively collected a patient's clinical record and imaging data to elucidate the natural progression, response to noninvasive treatment, and outcome of SSHH associated with HELLP syndrome. A 34-year-old woman, who underwent a cesarean section due to suspected fetal distress, developed SSHH accompanied by the potential risk of rupture and deteriorated serology within the first 24 hours after delivery. Emergency blood routine examination, serum biochemistry analysis, and computed tomography of the abdomen revealed a SSHH associated with HELLP syndrome. The main rescue measures included the use of corticosteroids, antihypertensive drugs, and platelet transfusion. A positive effect on the patient's condition was exhibited within 24 to 48 hours. The majority of the subcapsular hepatic hematoma could be absorbed without any sequelae over a period of 7 months. For patients with pregnancy-induced hypertension, there is a heightened risk of HELLP syndrome occurrence in subsequent pregnancies. The assessment and treatment of SSHH should be conducted by an experienced multidisciplinary team. In addition to timely delivery, the administration of corticosteroids, usage of antihypertensive medication, and platelet transfusion are necessary, particularly within the first 48 hours if the patient's condition permits. This approach would provide valuable insights for further therapeutic decisions and facilitate a preliminary prognosis assessment.