Nitrous oxide abuse direct measurement for diagnosis and follow-up: update on kinetics and impact on metabolic pathways.

Recreational use of nitrous oxide (N2O) has become a major health issue worldwide, with a high number of clinical events, especially in neurology and cardiology. It is essential to be able to detect and monitor N2O abuse to provide effective care and follow-up to these patients. Current recommendations for detecting N2O in cases of recreational misuse and consumption markers are lacking. We aimed to update current knowledge through a review of the literature on N2O measurement and kinetics. We reviewed the outcomes of experiments, whether in preclinical models (in vitro or in vivo), or in humans, with the aim to identify biomarkers of intoxication as well as biomarkers of clinical severity, for laboratory use. Because N2O is eliminated 5 min after inhalation, measuring it in exhaled air is of no value. Many studies have found that urine and blood matrices concentrations are connected to ambient concentrations, but there is no similar data for direct exposure. There have been no studies on N2O measurement in direct consumers. Currently, patients actively abusing N2O are monitored using effect biomarkers (biomarkers related to the effects of N2O on metabolism), such as vitamin B12, homocysteine and methylmalonic acid.

Calcium state estimation by total calcium: the evidence to end the never-ending story.

Background Total blood calcium (TCa) is routinely used to diagnose and manage mineral and bone metabolism disorders. Numerous laboratories adjust TCa by albumin, though literature suggests there are some limits to this approach. Here we report a large retrospective study on agreement rate between ionized calcium (iCa) measurement and TCa or albumin-adjusted calcium measurements. Methods We retrospectively selected 5055 samples with simultaneous measurements of iCa, TCa, albumin and pH. We subgrouped our patients according to their estimated glomerular filtration rate (eGFR), albumin levels and pH. We analyzed each patient's calcium state with iCa as reference to determine agreement rate with TCa and albumin-adjusted calcium using Payne, Clase, Jain and Ridefelt formulas. Results The Payne formula performed poorly in patients with abnormal albumin, eGFR or pH levels. In patients with low albumin levels or blood pH disorders, Payne-adjusted calcium may overestimate the calcium state in up to 80% of cases. Similarly, TCa has better agreement with iCa in the case of hypoalbuminemia, but performed similarly to the Payne formula in patients with physiological albumin levels. The global agreement rate for Clase, Jain and Ridefelt formulas suggests significant improvement compared to Payne calcium adjustment but no significant improvement compared to TCa. Conclusions Total and albumin-adjusted calcium measurement leads to a misclassification of calcium status. Moreover, accurate calcium state determination depends on blood pH levels, whose measurement requires the same pre-analytical restrictions as iCa measurement. We propose that iCa should instead become the reference method to determine the real calcium state.

Bile acid alterations in nonalcoholic fatty liver disease, obesity, insulin resistance and type 2 diabetes: what do the human studies tell?

PURPOSE OF REVIEW: The purpose of this review is to discuss the influence of obesity, insulin resistance, type 2 diabetes (T2D), and nonalcoholic fatty liver disease (NAFLD) on bile acid metabolism and to analyze whether these findings reinforce current beliefs about the role of bile acids in the pathophysiology of these diseases. RECENT FINDINGS: Discordant results on plasma bile acid alterations in NAFLD patients have been reported. Obesity, insulin resistance, and T2D, common comorbidities of NAFLD, have been associated with bile acid changes, but the individual bile acid species variations differ between studies (summarized in this review), perhaps because of clinicobiological differences between the studied patient populations and the heterogeneity of statistical analyses applied. SUMMARY: The regulatory role of bile acids in metabolic and cellular homeostasis renders bile acids attractive candidates as players in the pathophysiology of NAFLD. However, considering the complex relationship between NAFLD, obesity, insulin resistance and T2D, it is difficult to establish clear and independent associations between bile acid alterations and these individual diseases. Though bile acid alterations may not drive NAFLD progression, signaling pathways activated by bile acids remain potent therapeutic targets for its treatment. Further studies with appropriate matching or adjustment for potential confounding factors are necessary to determine which pathophysiological conditions drive the alterations in bile acid metabolism.

[An alarming health check-up: what a bloody plasma!] / Un bilan alarmant : un plasma sanglant !

A 35-year-old patient with a metabolic pathology was hospitalized for programmed fibroscopy under general anesthesia for investigation and management of portal hypertension. Following the operation, he showed signs of sepsis and was transferred to intensive care unit. Biological analyzes carried out and generated automaton alarms for certain parameters. A visual check of the appearance of the sample revealed an unusual color of plasma. Additional informations obtained from the clinical department did not provide any explanation for this coloration. Additional assays confirmed an overdose of vitamin B12 related to the treatment of his pathology and which is responsible for the interference observed. Hence the interest of checking the reaction curves in the event of suspected interference and, if necessary, of making dilutions in order to reduce the effects on the biological assays.

Understanding Neuropathy Features in the Context of Nitrous Oxide Abuse: A Combined Electrophysiological and Metabolic Approach.

BACKGROUND: The incidence of neurological complications associated with nitrous oxide (N2O) abuse, including N2O-induced myelopathy and neuropathy, has risen in the past decade. N2O-induced neuropathy often presents as a subacute axonal pathology; however, demyelinating patterns mimicking Guillain-Barré syndrome have also been observed. This study explores the metabolic pathophysiology of N2O-induced neuropathy, focusing on the alteration in metabolism to provide a deeper understanding of the biochemical pathways influencing the diverse electrophysiological patterns observed. METHODS: We conducted a combined metabolic and electrophysiological exploration of 35 patients who underwent electromyographic exams at our referral center over a three-year period for sensorimotor symptoms linked to recreational N2O use. We collected demographic, clinical, radiological, electrophysiological, and biological data. Patients were categorized into axonal or demyelinating groups based on their electrophysiological patterns, and metabolic parameters were compared. RESULTS: Our cohort predominantly exhibited a length-dependent sensorimotor axonal symmetrical neuropathy affecting the lower limbs. Among the patients, 40% met the demyelinating criteria, with four patients exhibiting conduction blocks. The demyelinating group had a significantly higher peripheral neuropathy disability (PND) score at diagnosis. Elevated homocysteine and methylmalonic acid (MMA) levels were noted in all patients, but these were lower in the demyelinating group. CONCLUSIONS: This study highlights the diverse electrophysiological manifestations of N2O-induced neuropathy and underscores the potential role of metabolic parameters as biomarkers to understand its pathophysiology. Lower hyperhomocysteinemia and MMA levels were observed in demyelinating patterns. In this study, we did not observe further improvement, but it is well-known that demyelinating features have a better prognosis related to the further remyelination. These findings contribute to a better understanding of N2O-related neuropathic damage and could guide future therapeutic interventions based on biochemical-neurophysiological stratifications.

Biomarkers for the diagnosis and monitoring of nitrous oxide intoxication: objectives and methodology of the SFBC Working Group.

The recreational use of nitrous oxide (N2O) is an emerging public health issue. Chronic N2O abuse may result in various clinical symptoms, encompassing neurological, psychiatric and cardiovascular outcomes. Despite the difficulties for the laboratory investigation of N2O intoxication, there is currently no guidelines in France to help both clinicians and biologists use appropriate biomarkers for the diagnosis and monitoring of patients with clinical symptoms potentially related to N2O intoxication. A multi-disciplinary Working Group, carried out under the auspices of the French Society of Clinical Biology (SFBC) and in collaboration with the French Societies of Emergency Medicine (SFMU), Analytical Toxicology (SFTA), Hemostasis and Thrombosis (SFTH), Vitamins and Biofactors (SFVB), and the French Federation of Neurology (FFN), was recently implemented to elaborate practical guidelines. The methodology of the Working Group is based on the critical analysis of the literature, and raising concerns and objectives are grouped into five working packages. The present manuscript primarily aims to expound upon the methodology and objectives of the ongoing SFBC Working Group on N2O.

Nitrous Oxide Abuse: Clinical Outcomes, Pharmacology, Pharmacokinetics, Toxicity and Impact on Metabolism.

The recreational use of nitrous oxide (N2O), also called laughing gas, has increased significantly in recent years. In 2022, the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) recognized it as one of the most prevalent psychoactive substances used in Europe. Chronic nitrous oxide (N2O) exposure can lead to various clinical manifestations. The most frequent symptoms are neurological (sensitive or motor disorders), but there are also other manifestations like psychiatric manifestations or cardiovascular disorders (thrombosis events). N2O also affects various neurotransmitter systems, leading to its anesthetic, analgesic, anxiolytic and antidepressant properties. N2O is very challenging to measure in biological matrices. Thus, in cases of N2O intoxication, indirect biomarkers such as vitamin B12, plasma homocysteine and plasma MMA should be explored for diagnosis and assessment. Others markers, like oxidative stress markers, could be promising but need to be further investigated.

Targeted Metabolomics Analysis Suggests That Tacrolimus Alters Protection against Oxidative Stress.

Tacrolimus (FK506) is an immunosuppressant that is experiencing a continuous rise in usage worldwide. The related side effects are known to be globally dose-dependent. Despite numerous studies on FK506, the mechanisms underlying FK506 toxicity are still not well understood. It is therefore essential to explore the toxicity mediated by FK506. To accomplish this, we conducted a targeted metabolomic analysis using LC-MS on the plasma samples of patients undergoing FK506 treatment. The aim was to identify any associated altered metabolic pathway. Another anti-calcineurin immunosuppressive therapy, ciclosporin (CSA), was also studied. Increased plasma concentrations of pipecolic acid (PA) and sarcosine, along with a decrease in the glycine/sarcosine ratio and a tendency of increased plasma lysine was observed in patients under FK506 compared to control samples. Patients under CSA do not show an increase in plasma PA compared to the control samples, which does not support a metabolic link between the calcineurin and PA. The metabolomics changes observed in patients under FK506 highlight a possible link between FK506 and the action of an enzyme involved in both PA and sarcosine catabolism and oxidative pathway, the Peroxisomal sarcosine oxidase (PIPOX). Moreover, PA could be investigated as a potential biomarker of early nephrotoxicity in the follow-up of patients under FK506.

Comparison of biomarker for diagnosis of nitrous oxide abuse: challenge of cobalamin metabolic parameters, a retrospective study.

BACKGROUND: Recreational use of nitrous oxide (N2O) leads to neurological disorders including combined subacute degeneration of spinal cord, psychological disorders, and thrombosis. Serum or urine N2O assays could not be routinely performed. Hence, it is necessary to investigate other biological markers such as metabolic markers. We aimed here to challenge the three main biological markers used for the diagnosis of nitrous oxide abuse as total vitamin B12, homocysteine, and methylmalonic acid. METHODS: We retrospectively collected clinical and biological data from 52 patients with known, documented chronic N2O abuse and associated clinical signs (peripheral neuropathy disability score or thrombosis event). Sera and plasma total vitamin B12, methylmalonic acid (MMA), and homocysteine were performed to identify the most specific marker of chronic N2O intoxication and related clinical outcomes. RESULTS: Plasma homocysteine was almost consistently increased in case of N2O chronic consumption, whereas MMA increase and total vitamin B12 decrease are not systematically found. Our results showed that none of the markers are correlated with levels of N2O consumptions. However, homocysteine and MMA are correlated with clinical severity, but MMA seems to be a better marker of clinical severity. CONCLUSION: There is no specific marker of nitrous oxide abuse according to levels of consumption, total vitamin B12 decrease could not be used either as consumption or as severity marker. However, we showed that homocysteine is consistently increased and could be used as marker of recent N2O consumption. On the other hand, we showed that MMA could be used as a marker of clinical gravity.

A case of pink urine associated with abdominal pain crisis / Un cas d'urines roses associées à des crises de douleurs abdominales

An adolescent girl consults a physician for abdominal pain attacks occurring regularly for 2 years. After eliminating gastroenterologic or gynecologic causes, an acute hepatic porphyria is suspected. The pink color of her urine seems consistent with the suspicion of porphyria; however, the urinary profile of porphyrins and its precursors is normal.

Une adolescente consulte son médecin pour des crises de douleurs abdominales survenant de manière régulière depuis environ 2 ans. Après avoir éliminé une étiologie gastro-intestinale ou gynécologique, une porphyrie aiguë hépatique est suspectée. Un bilan urinaire est alors réalisé. La coloration rose des urines est en faveur de cette hypothèse, cependant le profil urinaire des porphyrines et de ses précurseurs est normal, excluant une crise aiguë de porphyrie.