Pesticide butachlor exposure perturbs gut microbial homeostasis.

Agricultural production relies heavily on the use of pesticides, which may accumulate in soil and water, posing a significant threat to the global ecological environment and biological health. Butachlor is a commonly used herbicide and environmental pollutant, which has been linked to liver and kidney damage, as well as neurological abnormalities. However, the potential impact of butachlor exposure on the gut microbiota remains understudied. Thus, our aim was to investigate the potential negative effects of butachlor exposure on host health and gut microbiota. Our results demonstrated that butachlor exposure significantly reduced the host antioxidant capacity, as evidenced by decreased levels of T-AOC, SOD, and GSH-Px, and increased levels of MDA. Serum biochemical analysis also revealed a significant increase in AST and ALT levels during butachlor exposure. Microbial analysis showed that butachlor exposure significantly reduced the abundance and diversity of gut microbiota. Furthermore, butachlor exposure also significantly altered the gut microbial composition. In conclusion, our findings indicate that butachlor exposure can have detrimental health effects, including dysregulation of antioxidant enzymes, abnormalities in transaminases, and hepatointestinal damage. Furthermore, it disrupts the gut microbial homeostasis by altering microbial composition and reducing diversity and abundance. In the context of the increasingly serious use of pesticides, this study will help provide impetus for standardizing the application of pesticides and reducing environmental pollution.

Enzymatic Routes for Chiral Amine Synthesis: Protein Engineering and Process Optimization.

Chiral amines are essential motifs in pharmaceuticals, agrochemicals, and specialty chemicals. While traditional chemical routes to chiral amines often lack stereoselectivity and require harsh conditions, biocatalytic methods using engineered enzymes can offer high efficiency and selectivity under sustainable conditions. This review discusses recent advances in protein engineering of transaminases, oxidases, and other enzymes to improve catalytic performance. Strategies such as directed evolution, immobilization, and computational redesign have expanded substrate scope and enhanced efficiency. Furthermore, process optimization guided by techno-economic assessments has been crucial for establishing viable biomanufacturing routes. Combining state-of-the-art enzyme engineering with multifaceted process development will enable scalable, economical enzymatic synthesis of diverse chiral amine targets.

Reported Adverse Events in a Multicenter Cohort of Patients Ages 6-18 Years with Cystic Fibrosis and at Least one F508del Allele Receiving Elexacaftor/Tezacaftor/Ivacaftor.

OBJECTIVE: To describe reported adverse events (AEs) associated with elexacaftor/tezacaftor/ivacaftor (ETI) in a pediatric sample with cystic fibrosis (CF) aged 6-18 years, with at least one F508del variant, followed at multiple Italian CF centers. STUDY DESIGN: This was a retrospective, multicenter, observational study. All children receiving ETI therapy from October 2019 to December 2023 were included. We assessed the prevalence and type of any reported potential drug-related AEs, regardless of discontinuation necessity. Persistent AEs were defined as those continuing at the end of the observation period. RESULTS: Among 608 patients on ETI, 109 (17.9%) reported at least one AE. The majority (N=85, 77.9%) were temporary, with a median duration of 11 days (range 1-441 days). Only 7 (1.1%) patients permanently discontinued treatment, suggesting good overall safety of ETI. The most common AEs leading to discontinuation were transaminase elevations (temporary 14.1%, persistent 25.9%) and urticaria (temporary 41.2%, persistent 7.4%). Creatinine phosphokinase elevation was uncommon. No significant differences in AEs were observed based on sex, age groups (6-11 vs. 12-18 years), or genotype. Pre-existing CF-related liver disease was associated with an increased risk of transaminase elevations. We identified significant variability in the percentage of reported AEs (ANOVA p-value 0·026). CONCLUSIONS: This real-world study highlights significant variability in reported AEs. Our findings suggest that ETI is a safe and well-tolerated therapy in children and adolescents with CF. However, further long-term safety and effectiveness investigations are warranted.

The Liver and Lysosomal Storage Diseases: From Pathophysiology to Clinical Presentation, Diagnostics, and Treatment.

The liver, given its role as the central metabolic organ, is involved in many inherited metabolic disorders, including lysosomal storage diseases (LSDs). The aim of this manuscript was to provide a comprehensive overview on liver involvement in LSDs, focusing on clinical manifestation and its pathomechanisms. Gaucher disease, acid sphingomyelinase deficiency, and lysosomal acid lipase deficiency were thoroughly reviewed, with hepatic manifestation being a dominant clinical phenotype. The natural history of liver disease in the above-mentioned lysosomal disorders was delineated. The importance of Niemann-Pick type C disease as a cause of cholestatic jaundice, preceding neurological manifestation, was also highlighted. Diagnostic methods and current therapeutic management of LSDs were also discussed in the context of liver involvement.

Naturalistic comparison of clomethiazole and Diazepam treatment in alcohol withdrawal: effects on oxidative stress, inflammatory cytokines and hepatic biomarkers.

Ethanol is metabolized by alcohol dehydrogenase to acetaldehyde and induces cytochrome P450 2E1 (CYP2E1), which generates reactive oxygen species that cause inflammatory liver damage. Clomethiazole, a drug approved for alcohol withdrawal treatment (AWT) in some European countries, inhibits CYP2E1. We hypothesized that clomethiazole would lead to a faster reduction in oxidative stress, inflammatory cytokines, and liver enzymes compared to diazepam treatment. We analysed respective biomarkers in 50 patients undergoing AWT and 25 healthy individuals but found no statistical difference between the two medication groups over 3-5 days. Hence, our hypothesis was not confirmed during this observation period.

Whole-exome sequencing for genetic diagnosis of idiopathic liver injury in children.

Genome-wide approaches, such as whole-exome sequencing (WES), are widely used to decipher the genetic mechanisms underlying inter-individual variability in disease susceptibility. We aimed to dissect inborn monogenic determinants of idiopathic liver injury in otherwise healthy children. We thus performed WES for 20 patients presented with paediatric-onset recurrent elevated transaminases (rELT) or acute liver failure (ALF) of unknown aetiology. A stringent variant screening was undertaken on a manually-curated panel of 380 genes predisposing to inherited human diseases with hepatobiliary involvement in the OMIM database. We identified rare nonsynonymous variants in nine genes in six patients (five rELT and one ALF). We next performed a case-level evaluation to assess the causal concordance between the gene mutated and clinical symptoms of the affected patient. A genetic diagnosis was confirmed in four rELT patients (40%), among whom two carried novel mutations in ACOX2 or PYGL, and two had previously-reported morbid variants in ABCB4 or PHKA2. We also detected rare variants with uncertain clinical significance in CDAN1, JAG1, PCK2, SLC27A5 or VPS33B in rELT or ALF patients. In conclusion, implementation of WES improves diagnostic yield and enables precision management in paediatric cases of liver injury with unknown aetiology, in particular recurrent hypertransaminasemia.

Daño hepático inducido por uso de anticonceptivos orales en una paciente con ictericia prolongada y transaminasas elevadas: reporte de caso / Drug-induced liver injury secondary to the use of oral contraceptives in a patient with prolonged jaundice and elevated transaminases: Case report

La hepatotoxicidad inducida por medicamentos es un diagnóstico de descarte. Típicamente, se presenta en pacientes que desarrollan cambios clínicos y bioquímicos compatibles con hepatitis, pero relacionados con el inicio reciente de agentes farmacológicos, y que se resuelven tras el retiro de la noxa. Su desarrollo se ha descrito con el uso de algunos antibióticos, antituberculosos, estatinas, herbolarios y antiinflamatorios no esteroideos; sin embargo, hay pocos reportes de casos con el uso de anticonceptivos orales, en los cuales el surgimiento de mecanismos idiosincráticos puede llevar a la presentación de características clínicas como ictericia y anormalidades en los exámenes de laboratorio, como la elevación de las transaminasas. Esto requiere de estudios extensos para descartar otras patologías que pueden presentarse de esta forma, lo que representa un reto clínico. En este artículo se muestra el reporte de un caso de una paciente con antecedente de uso crónico de anticonceptivos implantables y que, tras el ajuste de la terapia con el inicio de anticonceptivos orales, desarrolla un episodio de elevación marcada de transaminasas e ictericia.

Drug-induced liver injury is a rule-out diagnosis. Typically, it occurs in patients who develop clinical and biochemical changes compatible with hepatitis, but related to a history of recent onset of pharmacological agents, and resolves after withdrawal of the noxious substances. Its development has been described with the use of some antibiotics, antituberculosis agents, statins, herbal and nonsteroidal anti inflammatory drugs; however, there are few reports of cases with the use of oral contraceptives, in which the appearance of idiosyncratic mechanisms can lead to the presentation of clinical features such as jaundice and laboratory tests abnormalities, like transaminase elevation, requiring extensive studies to rule out other pathologies that may have this clinical presentation, wich represents a clinical challenge. We present a case report of a patient who had chronic use of implantable contraceptives and who, after adjustment of therapy with the start of oral contraceptives, developed an episode of marked elevation of transaminases and jaundice.

Shwachman-Diamond syndrome mimicking mitochondrial hepatopathy.

Shwachman-Diamond syndrome (SDS) is a genetic disorder caused by mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene. The syndrome is characterized by multiorgan dysfunction primarily involving the bone marrow and exocrine pancreas. Frequently overlooked is the hepatic dysfunction seen in early childhood which tends to improve by adulthood. Here, we report a child who initially presented with failure to thrive and elevated transaminases, and was ultimately diagnosed with SDS. A liver biopsy electron micrograph revealed hepatocytes crowded with numerous small mitochondria, resembling the hepatic architecture from patients with inborn errors of metabolism, including mitochondrial diseases. To our knowledge, this is the first report of the mitochondrial phenotype in an SDS patient. These findings are compelling given the recent cellular and molecular research studies which have identified SBDS as an essential regulator of mitochondrial function and have also implicated SBDS in the maintenance of mitochondrial DNA.

Analysis of dietary fats intake and lipid profile in Chilean patients with glucose transport type 1 deficiency syndrome: similarities and differences with the reviewed literature.

Introduction: Glucose transporter type 1 deficiency syndrome (GLUT1-DS) is a neurological disorder caused by mutations in the SLC2A1 gene. The main treatment is ketogenic diet therapy (KDT), which changes the brain's energy substrate from glucose to ketone bodies. The diet controls seizures, but there may be side effects such as dyslipidemia. This study aimed to describe the type of fats ingested by the Chilean cohort of patients with GLUT1-DS and analyze for alterations in the lipid profile. Methods: A GLUT1-DS group and a control group were formed, each with 13 subjects who were matched by age, gender, and nutritional status. Anthropometry, dietary intake, including types of fat, and blood tests were evaluated (lipid and liver profile, and 25-hydroxyvitamin D levels). Results: A high-fat diet, especially saturated fat, was identified in the GLUT1-DS group (38% of total calories), with the use of medium-chain triglycerides (17% of total calories). In addition, GLUT1-DS participants had a higher intake of monounsaturated (MUFA) and polyunsaturated (PUFA) fats and adequate consumption of omega-3 (2% of total calories). Despite the GLUT1-DS group receiving on average 80% of its total energy as fats, it is important to highlight that 50% are MUFA+PUFA fats, there were no significant differences in the lipid and liver profile compared to the control group. Conclusion: KDT did not negatively impact lipid profile, despite a high intake of fats. It is important to monitor lipid profiles, in a personalized and constant manner, to prevent future nutritional risks.

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.

Introduction: 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. Objectives: To determine the association of liver transaminases with pregnancy outcomes in ICP and evaluate critical levels for prediction of adverse outcomes. Material and Methods: 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. Results: 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. Conclusion: ICP leads to adverse pregnancy outcomes. ALT is a promising predictor of adverse outcome and termination of pregnancy can be planned accordingly.

Starvation hepatitis and refeeding-induced hepatitis: mechanism, diagnosis, and treatment.

Anorexia nervosa (AN) is one of the most common psychiatric disorders among young adults and is associated with a substantial risk of death from suicide and medical complications. Transaminase elevations are common in patients with AN at the time of hospital admission and have been associated with longer lengths of hospital stay. Multiple types of hepatitis may occur in these patients, including two types that occur only in patients with AN: starvation hepatitis and refeeding-induced hepatitis. Starvation hepatitis is characterized by severe transaminase elevation in patients in the advanced phase of protein-energy deprivation and is associated with complications of severe starvation, such as hypoglycaemia, hypothermia, and hypotension. Refeeding-induced hepatitis is characterized by a milder increase in transaminases that occurs in the early refeeding phase and is associated with hypophosphatemia, hypokalemia, and hypomagnesaemia. Among the most common forms of hepatitis, drug-induced liver injury is particularly relevant in this patient cohort, given the frequent use and abuse of methamphetamines, laxatives, antidepressants, and antipsychotics. In this review, we provided an overview of the different forms of anorexic-associated hepatitis, a diagnostic approach that can help the clinician to correctly frame the problem, and indications on their management and treatment.

The biochemical pattern defines MASLD phenotypes linked to distinct histology and prognosis.

BACKGROUND: MASLD can manifest as hepatocellular damage, which can result in mild elevation of aminotransferases. However, in some patients, MASLD presents with cholestatic pattern. OBJECTIVE: To assess the impact of the biochemical pattern on the natural course of MASLD, including liver damage in histology, the accuracy of non-invasive tests(NITs), and prognosis. METHODS: Multicenter study enrolling 2156 patients with biopsy-proven MASLD, who were classified based on their[ALT/ULN)]/[(ALP/ULN)] levels at the time of biopsy: (a) hepatocellular pattern(H), > 5; (b) mixed pattern(M),2-5; (c) cholestatic pattern(C), < 2. OUTCOMES: (a) histological evaluation of the single components of NAS, MASH, and fibrosis; (b) NITs and transient elastography assessing advanced fibrosis; (c) prognosis determined by the appearance of decompensated cirrhosis and death. RESULTS: Out of the 2156 patients, 22.9% exhibited the H-pattern, whilst 31.7% exhibited the C-pattern. Severe steatosis, ballooning, lobular inflammation, and MASH (56.4% H vs. 41.9% M vs. 31.9% C) were more common in H-pattern (p = 0.0001),whilst C-pattern was linked to cirrhosis (5.8% H vs. 5.6% M vs. 10.9% C; p = 0.0001). FIB-4(0.74(95% CI 0.69-0.79) vs. 0.83 (95% CI 0.80-0.85); p = 0.005) and Hepamet Fibrosis Score(0.77 (95% CI 0.69-0.85) vs. 0.84 (95% CI 0.80-0.87); p = 0.044)exhibited lower AUROCs in the H-pattern. The C-pattern[HR 2.37 (95% CI 1.12-5.02); p = 0.024], along with age, diabetes, and cirrhosis were independently associated with mortality. Most patients maintained their initial biochemical pattern during the second evaluation. CONCLUSIONS: The H-pattern exhibited greater necro-inflammation in the histology than the C-pattern, whereas the latter showed more cirrhosis. The accuracy of NITs in detecting fibrosis was decreased in H-pattern. The occurrence of decompensated events and mortality was predominant in C-pattern. Therefore, identifying MASLD phenotypes based on the biochemical presentation could be relevant for clinical practice.

De Ritis Ratio to Predict Clinical Outcomes of Intermediate- and High-Risk Pulmonary Embolisms.

Background: Abnormal liver function tests can identify severe cardiopulmonary failure. The aspartate transaminase/alanine transaminase (AST/ALT) ratio, or the De Ritis ratio, is commonly used to evaluate acute liver damage. However, its prognostic value in pulmonary embolism (PE) is unknown. Methods: Two cohorts, including patients with intermediate- and high-risk PEs, were established: one with an abnormal baseline AST/ALT ratio (>1) and another with a normal baseline AST/ALT ratio (<1). The primary outcome was a 60-day mortality. Secondary outcomes included peak N-terminal pro-brain-natriuretic-peptide (NT-proBNP) levels, complications, and the need for critical care treatment. To assess the effect of abnormal AST/ALT ratios, inverse probability weighted (IPW) analyses were performed. Results: In total, 230 patients were included in the analysis, and 52 (23%) had an abnormal AST/ALT ratio. After the IPW correction, patients with an abnormal AST/ALT ratio had a significantly higher mortality rate and peak NT-proBNP levels. The relative risks of 60-day mortality, shock development, use of inotropes/vasopressors, mechanical ventilation, and extracorporeal life support were 9.2 (95% confidence interval: 3.3-25.3), 10.1 (4.3-24), 2.7 (1.4-5.2), 2.3 (1.4-3.7), and 5.7 (1.4-23.1), respectively. Conclusions: The baseline AST/ALT ratio can be a predictor of shock, multiorgan failure, and mortality in patients with a pulmonary embolism.

Corrigendum: Hematological profile, inflammatory markers and serum liver enzymes in COVID 19 positive children vs. COVID 19 negative ones-a comparative study.

[This corrects the article DOI: 10.3389/fped.2024.1334591.].

Subnormal Serum Liver Enzyme Levels: A Review of Pathophysiology and Clinical Significance.

Subnormal levels of liver enzymes, below the lower limit of normal on local laboratory reports, can be useful diagnostically. For instance, subnormal levels of aminotransferases can be observed in vitamin B6 deficiency and chronic kidney disease. Subnormal alkaline phosphatase levels may indicate the presence of hypophosphatasia, Wilson's disease, deficiencies of divalent ions, or malnutrition. Subnormal levels of gamma glutamyl transferase may be seen in cases of acute intrahepatic cholestasis, the use of certain medications, and in bone disease. Finally, subnormal levels of 5'-nucleotidase have been reported in lead poisoning and nonspherocytic hemolytic anemia. The aim of this review is to bring attention to the fact that subnormal levels of these enzymes should not be ignored as they may indicate pathological conditions and provide a means of early diagnosis.

Poorly controlled pediatric type 1 diabetes mellitus is a risk factor for metabolic dysfunction associated steatotic liver disease (MASLD): An observational study.

OBJECTIVES: Recent studies have suggested a link between type 1 diabetes mellitus (T1D) and metabolic dysfunction associated steatotic liver disease (MASLD) in children and adolescent, but longitudinal evidence is lacking. This study aimed to investigate the potential association between poorly controlled T1D and elevated alanine aminotransferase (ALT), serving as a proxy for MASLD in children and adolescents over time. METHODS: The study included 32,325 children aged 2-17 years with T1D from Germany, Austria, and Switzerland who had undergone at least one assessment of liver enzyme levels recorded in the Diabetes-Patienten- Verlaufsdokumentation registry. Multivariable logistic and Cox regression models were calculated to show possible associations between T1D and elevated ALT values (>26 U/L in males, >22 U/L in females) as a proxy for MASLD. RESULTS: Children with poorly controlled T1D (HbA1c > 11%) exhibited increased odds of elevated ALT values, after adjustment for age, sex, diabetes duration and overweight (odds ratio [OR] 2.54; 95% confidence interval [CI], 2.10-3.10; p < 0.01). This finding is substantiated by a longitudinal analysis, which reveals that inadequately controlled T1D was associated with a higher hazard ratio (HR) of elevated ALT values compared to children with controlled T1D over an observation period extending up to 5.5 (HR: 1.54; 95% CI, 1.19-2.01; p < 0.01). CONCLUSION: In conclusion, the current study strongly links poorly controlled T1D in children and adolescents to MASLD irrespective of overweight. This association is not only present cross-sectionally but also increases over time. The study underscores the critical role of effective diabetes management in reducing the risk of MASLD in this population.

Tuberculosis in a Liver Cirrhosis Patient: A Management Conundrum.

This case report delves into the intricate challenges of managing tuberculosis (TB) in a 70-year-old male with decompensated chronic liver disease (DCLD) and a history of endoscopic variceal ligation. The patient, initially presenting with symptoms such as black-colored stools, breathlessness, and weight loss, was diagnosed with right-sided pneumonia alongside DCLD. Despite the administration of standard beta-lactam plus macrolide antibiotics, the patient exhibited no improvement. Subsequent bronchoscopy revealed Mycobacterium tuberculosis (MTB), prompting the initiation of first-line anti-tubercular therapy. However, the hepatotoxic response necessitated a switch to a modified regimen with non-hepatotoxic drugs, emphasizing the challenge of managing TB in cirrhotic patients. Effective management of MTB infection involves personalized administration of anti-TB drugs, taking into account the individual's chronic liver disease status. This case underscores the importance of treating tuberculosis in liver cirrhosis patients based on the Child-Turcotte-Pugh score. A tailored and vigilant approach is indispensable for the successful management of MTB infection.

Hepatitis B in Pediatric Population: Observational Retrospective Study in Romania.

Hepatitis B virus (HBV) is a frequent cause of chronic hepatitis worldwide, with an estimated 5.6 million children under 5 years being infected. In Romania, there are no available epidemiology reports on large cohorts in children. We aimed to assess the profile of pediatric chronic HBV infection in southern Romania. We conducted an observational retrospective study on 506 HBV-infected children. Based on alaninaminotransferase (ALT), HBV serology and viremia, we identified four states of the disease. We correlated age, gender, household HBV infection, coinfection with other viruses and laboratory parameters. Most patients were in a positive HBV envelope antigen (HBeAg) immune-active state (65.4%). Age at diagnosis was significantly lower for those with household infection (p < 0.05). ALT values were not significantly different between positive or negative HBeAg patients in the immune-active state (p = 0.780). ALT values were higher in patients with hepatitis D virus (HDV)-associated infection (p < 0.001). Children with a household HBV infection had a high viraemia more frequently when compared to those with no infected relative (79.3% vs. 67.4%) (p < 0.001), but the ALT values were not significantly different (p = 0.21). Most of the patients are in an immune-active state (high ALT, high viremia). The percentages of HBV- and HDV-associated infections are high, but lower than the reported prevalence in Romania in the general population.

Hematological profile, inflammatory markers and serum liver enzymes in COVID 19 positive children vs. COVID 19 negative ones-a comparative study.

Background: Complete blood count, C-reactive protein and transaminases are routine laboratory parameters investigated in children with infections, including COVID 19. We aimed to evaluate the diagnostic accuracy of these parameters in children diagnosed with COVID 19. Methods: At the time of admission, children with COVID 19 suggestive symptoms were tested RT-PCR for SARS CoV-2 and were allocated to either the study group (RT-PCR SARS CoV-2 positive) or control group (RT-PCR SARS CoV-2 negative). All children were evaluated by complete blood count, CRP, and transaminases. Results: When comparing the two groups, we identified significantly lower values for leukocytes (p < 0.001), neutrophils (p < 0.001), lymphocytes (p < 0.001) and thrombocytes (p = 0.014), but no significantly different values for CRP (p = 0.916) and monocytes (p = 0.082). A diagnostic score for COVID-19 was compiled using the abovementioned parameters-presence of fever, number of lymphocytes and aspartate-aminotransferase. Performance was tested, showing a positive discrimination value (AUC of 0.703)-81.5% sensitivity, 50.6% specificity. Conclusions: The leukocytes, neutrophils and lymphocytes have significantly lower values in COVID-19 children. The proposed score based on the presence of fever the values of lymphocytes and AST has a good sensitivity in predicting COVID-19 infection.