Elevated preoperative blood pressure and its relationship to intraoperative mean arterial pressure and blood loss in posterior spinal fusion for adolescent idiopathic scoliosis.

PURPOSE: The relationship between preoperative blood pressure (BP) and intraoperative mean arterial pressure (MAP) and estimated blood loss (EBL) in pediatric spine surgery is currently unknown. The objectives of this study were to determine if elevated preoperative BP is associated with elevated intraoperative MAP, EBL, and percentage estimated blood volume (EBV) lost, and to determine if intraoperative MAP is associated with percentage of EBV lost during posterior spinal fusion (PSF) for adolescent idiopathic scoliosis (AIS). METHODS: This is a retrospective cohort analysis of 209 patients undergoing PSF for AIS between 2016 and 2019 by a single surgeon. Data extracted included demographic characteristics, preoperative systolic and diastolic BP, continuous intraoperative MAP measured by arterial line, EBL, radiographic, and surgical characteristics. Time points of interest for MAP included incision and exposure. Elevated BP was defined as > 1 standard deviation above the mean BP of patients included in the study, and elevated MAP was defined as > 65 mmHg. RESULTS: Elevated preoperative systolic BP was associated with elevated MAP at incision (p = 0.002). Patients with elevated preoperative diastolic BP had significantly higher MAP at exposure and throughout the procedure (p = 0.04). MAP > 65 at incision was associated with a 5% increase in EBV lost (p < 0.001). CONCLUSIONS: Patients with elevated preoperative BP parameters have increased MAPs at incision, exposure, and throughout surgery. Elevated MAP at incision is associated with an increased percentage of EBV lost in a small number of patients undergoing PSF for AIS.

Mechanisms of nonalcoholic steatohepatitis-associated cardiomyopathy: key roles for liver-heart crosstalk.

PURPOSE OF REVIEW: Nonalcoholic steatohepatitis (NASH) is a multisystem disease that affects not only the liver but also heart, pancreas, and kidney. We currently lack a comprehensive understanding of mechanisms responsible for the development of NASH-associated cardiomyopathy or the influence of sex on pathophysiology. There is a critical need to address these gaps in knowledge in order to accelerate translation of knowledge into clinical practice. RECENT FINDINGS: NASH and cardiovascular disease share common risk factors such as chronic inflammation, hyperlipidemia, and insulin resistance. Early cardiac dysfunction in NASH that is independent of obesity or other cardiometabolic risk factors suggests roles for liver-heart crosstalk in disease pathogenesis. Inflammation is a driving force in the pathogenesis of NASH, and it is likely that 'spill over' of NASH inflammation contributes to the development of cardiomyopathy. However, molecular and cellular mechanisms that mediate NASH-associated cardiomyopathy remain unclear because of inherent limitations of experimental models. Even so, recent studies implicate inflammatory, metabolic, and physiologic mechanisms that enhance our understanding of NASH-associated cardiomyopathy and the role of liver-heart crosstalk. SUMMARY: An innovative, detailed, and mechanistic understanding of NASH-associated cardiomyopathy is relevant to public health and will be fundamental for the comprehensive care of these patients.

The Role of Hypoxia-Induced Mitogenic Factor in Organ-Specific Inflammation in the Lung and Liver: Key Concepts and Gaps in Knowledge Regarding Molecular Mechanisms of Acute or Immune-Mediated Liver Injury.

Hypoxia-induced mitogenic factor (HIMF), which is also known as resistin-like molecule α (RELM-α), found in inflammatory zone 1 (FIZZ1), or resistin-like alpha (retlna), is a cysteine-rich secretory protein and cytokine. HIMF has been investigated in the lung as a mediator of pulmonary fibrosis, inflammation and as a marker for alternatively activated macrophages. Although these macrophages have been found to have a role in acute liver injury and acetaminophen toxicity, few studies have investigated the role of HIMF in acute or immune-mediated liver injury. The aim of this focused review is to analyze the literature and examine the effects of HIMF and its human homolog in organ-specific inflammation in the lung and liver. We followed the guidelines set by PRISMA in constructing this review. The relevant checklist items from PRISMA were included. Items related to meta-analysis were excluded because there were no randomized controlled clinical trials. We found that HIMF was increased in most models of acute liver injury and reduced damage from acetaminophen-induced liver injury. We also found strong evidence for HIMF as a marker for alternatively activated macrophages. Our overall risk of bias assessment of all studies included revealed that 80% of manuscripts demonstrated some concerns in the randomization process. We also demonstrated some concerns (54.1%) and high risk (45.9%) of bias in the selection of the reported results. The need for randomization and reduction of bias in the reported results was similarly detected in the studies that focused on HIMF and the liver. In conclusion, we propose that HIMF could be utilized as a marker for M2 macrophages in immune-mediated liver injury. However, we also detected the need for randomized clinical trials and additional experimental and human prospective studies in order to fully comprehend the role of HIMF in acute or immune-mediated liver injury.

The Role of Pro-Inflammatory and Regulatory Signaling by IL-33 in the Brain and Liver: A Focused Systematic Review of Mouse and Human Data and Risk of Bias Assessment of the Literature.

Interleukin (IL)-33 is a member of the IL-1 family of proteins that have multiple roles in organ-specific inflammation. Many studies suggest diagnostic and therapeutic implications of this cytokine. Many studies have reported pro-inflammatory roles for IL-33 in innate immune responses involving the heart and lung. Recent studies also describe pro-inflammatory and regulatory roles for IL-33 in the pathogenesis of brain and liver disorders in addition to regulatory roles for this cytokine in the heart and lung. In this focused systematic review, we will review the literature regarding pro-inflammatory and regulatory effects of IL-33 in the brain and liver. We will also assess the potential risk of bias in the published literature in order to uncover gaps in the knowledge that will be useful for the scientific community. We utilized guidelines set by preferred reporting items for systemic reviews and meta-analyses. The electronic database was PubMed. Eligibility criteria included organ-specific inflammation in mice and humans, organ-specific inflammation in the central nervous and hepatic systems, and IL-33. Outcomes were pro-inflammatory or regulatory effects of IL-33. Risk of bias in individual studies and across studies was addressed by adapting the Cochrane Rob 2.0 tool. We discovered that a source of bias across the studies was a lack of randomization in human studies. Additionally, because the majority of studies were performed in mice, this could be perceived as a potential risk of bias. Regarding the central nervous system, roles for IL-33 in the development and maturation of neuronal circuits were reported; however, exact mechanisms by which this occurred were not elucidated. IL-33 was produced by astrocytes and endothelial cells while IL-33 receptors were expressed by microglia and astrocytes, demonstrating that these cells are first responders for IL-33; however, in the CNS, IL-33 seems to induce Th1 cytokines such as IL-1ß and TNF-α chemokines such as RANTES, MCP-1, MIP-1α, and IP-10, as well as nitric oxide. In the liver, similar risks of bias were determined because of the lack of randomized controlled trials in humans and because the majority of studies were performed in mice. Interestingly, the strain of mouse utilized in the study seemed to affect the role of IL-33 in liver inflammation. Lastly, similar to the brain, IL-33 appeared to have ST2-independent regulatory functions in the liver. Our results reveal plausible gaps in what is known regarding IL-33 in the pathogenesis of brain and liver disorders. We highlight key studies in the lung and heart as examples of advancements that likely occurred because of countless basic and translational studies in this area. More research is needed in these areas in order to assess the diagnostic or therapeutic potential of IL-33 in these disorders.

Incidence of Fractures From Perioperative Blood Pressure Cuff Use, Tourniquet Use, and Patient Positioning in Osteogenesis Imperfecta.

BACKGROUND: Osteogenesis imperfecta (OI) is a rare connective tissue disease with varying severity. Patients with OI are highly susceptible to skeletal fractures. Optimal perioperative management of these patients is not well defined. We investigated the risks associated with intraoperative use of noninvasive blood pressure (NIBP) cuffs, tourniquets, and intra-arterial catheters, and patient positioning in children with OI. METHODS: We retrospectively reviewed records of patients younger than 21 years with OI who underwent surgery with general anesthesia from 2010 to 2016 at our tertiary care center. The primary outcome of interest was iatrogenic fracture caused by NIBP cuff use, tourniquet use, or patient positioning. The secondary outcome of interest was complications associated with intra-arterial catheter use. RESULTS: Thirty-seven patients (15 girls) with a mean age of 10±4.8 years underwent 96 orthopaedic procedures (lower extremity, upper extremity, and spine) and 2 nonorthopaedic procedures (myringotomy, dental rehabilitation). Blood pressure was monitored with NIBP cuffs in 81 surgeries and intra-arterial catheters in 17 surgeries. Tourniquets (all applied to the lower extremity at a pneumatic pressure of 250 mm Hg) were used to minimize bleeding in 30 surgeries. There were no iatrogenic fractures associated with NIBP cuff use. One patient had a left humerus fracture that occurred during preoperative patient positioning. There were no fractures associated with tourniquet use and no complications related to intra-arterial catheters. CONCLUSIONS: In pediatric patients with OI, intraoperative use of NIBP cuffs and tourniquets was not associated with iatrogenic fracture. There were no complications related to intra-arterial catheter use. Care should be used during the perioperative period to prevent fractures during body positioning. LEVEL OF EVIDENCE: Level IV.

Why No Signals? Cerebral Anatomy Predicts Success of Intraoperative Neuromonitoring During Correction of Scoliosis Secondary to Cerebral Palsy.

BACKGROUND: Intraoperative neuromonitoring (IONM) is widely used to reduce postoperative neurological complications during scoliosis correction. IONM allows intraoperative detection of neurological insults to the spinal cord and enables surgeons to react in real time. IONM failure rates can reach 61% in patients with cerebral palsy (CP). Factors decreasing the quality of IONM signals or making IONM impossible in CP patients undergoing scoliosis correction have not been well described. METHODS: We categorized IONM data from 206 children with CP who underwent surgical scoliosis correction at a single institution from 2002 through 2013 into 3 groups: (1) "no signals," if neither somatosensory-evoked potentials (SSEP) nor transcranial motor-evoked potentials (TcMEP) could be obtained; (2) "no sensory," if no interpretable SSEP were obtained regardless of interpretable TcMEP; and (3) "no motor," if no interpretable TcMEP were obtained regardless of interpretable SSEP. We analyzed preexisting neuroimaging, available for 93 patients, and neurological status of the full cohort against these categories. Statistical analysis of univariate and multivariate associations was performed using logistic regression. Odds ratios (ORs) were calculated with significance set at P<0.05. RESULTS: Multivariate analysis showed significant associations of periventricular leukomalacia (PVL), hydrocephalus, and encephalomalacia with lack of meaningful and interpretable signals. Focal PVL (Fig. 1) was associated with no motor (OR=39.95; P=0.04). Moderate hydrocephalus was associated with no signals (OR=32.35; P<0.01), no motor (OR=10.14; P=0.04), and no sensory (OR=8.44; P=0.03). Marked hydrocephalus (Fig. 2) was associated with no motor (OR=20.46; P<0.01) and no signals (OR=8.83; P=0.01). Finally, encephalomalacia (Fig. 3) was associated with no motor (OR=6.99; P=0.01) and no signals (OR=4.26; P=0.03). CONCLUSION: Neuroanatomic findings of PVL, hydrocephalus, and encephalomalacia are significant predictors of limited IONM signals, especially TcMEP. LEVEL OF EVIDENCE: Level IV.

Incidence of and Risk Factors for Loss of 1 Blood Volume During Spinal Fusion Surgery in Patients With Cerebral Palsy.

BACKGROUND: Spinal fusion surgery is associated with greater blood loss in patients with cerebral palsy (CP) than in patients with adolescent idiopathic scoliosis. Risk factors for loss of 1 blood volume (LOBV) in patients with CP have not been well studied. We investigated the incidence of and risk factors for LOBV during spinal fusion surgery in young patients with CP. METHODS: We queried a multicenter registry of CP patients for all patients 21 years or younger who had undergone spinal fusion from 2008 through 2013; 272 patients met these criteria. We analyzed data on patient characteristics, preoperative laboratory values, radiographic measures, and surgical characteristics. For univariate analysis, we used χ tests and logistic regression models. Factors that were significant in the univariate analysis were used to construct a multivariate logistic regression model. Significance was set at P<0.01. RESULTS: Incidence of LOBV was 39.7%. On multivariate analysis, unit rod construct and coronal curve magnitude were significantly associated with LOBV (P<0.01). The multivariate model accounted for 32.2% of variance in LOBV. Compared with patients with pedicle screw-rod constructs, patients with unit rod constructs had 12.6-fold higher odds of LOBV (P<0.01). For each 1-degree increase in coronal curve magnitude, odds of LOBV increased 1.03-fold (P<0.01). CONCLUSIONS: In patients with CP, there is a substantial risk of LOBV during spinal fusion surgery. Use of unit rod constructs and greater preoperative coronal curves were significant risk factors for LOBV during surgery. LEVEL OF EVIDENCE: Level II.

Drug-induced hepatotoxicity: metabolic, genetic and immunological basis.

Drug-induced hepatotoxicity is a significant cause of acute liver failure and is usually the primary reason that therapeutic drugs are removed from the commercial market. Multiple mechanisms can culminate in drug hepatotoxicity. Metabolism, genetics and immunology separately and in concert play distinct and overlapping roles in this process. This review will cover papers we feel have addressed these mechanisms of drug-induced hepatotoxicity in adults following the consumption of commonly used medications. The aim is to generate discussion around "trigger point" papers where the investigators generated new science or provided additional contribution to existing science. Hopefully these discussions will assist in uncovering key areas that need further attention.

Sexual dimorphism in hepatic PPAR alpha and CYP4a12a expression is associated with reduced development of drug-induced non-alcoholic steatohepatitis in female IL-33-/- mice.

Males are at higher risk for developing metabolic dysfunction-associated steatohepatitis (MASH) than females; however, mechanisms mediating sexual dimorphism in MASH development are not completely understood. Nutrition-based mouse models suggest that dysregulated fatty acid biosynthesis promotes MASH. Drugs recapitulate MASH without diet variabilities. This brief report investigates associations of sexual dimorphism with male susceptibility to MASH utilizing a drug-induced MASH model and focuses on very-long-chain fatty acid biosynthesis pathways. We assessed male and female mouse livers at 5 and 15 weeks following MASH induction by immunizations and age-matched un-immunized controls utilizing Western blot. Our results suggest that PPAR alpha and CYP4a12a protect females, while CYP4v2 does not protect males from MASH development. Our results have important implications for understanding sexual dimorphism in the pathogenesis of MASH.

A retrospective identification of gastroesophageal reflux disease as a new risk factor for surgical site infection in cerebral palsy patients after spine surgery.

BACKGROUND: Neuromuscular scoliosis is a known risk factor for surgical site infection (SSI) after spinal fusion, with reported infection rates as high as 11.2%. Although risk factors such as antibiotic timing have been previously addressed, our objective was to identify intrinsic risk factors for SSI in cerebral palsy (CP) patients with neuromuscular scoliosis. We hypothesized that CP patients who develop SSI after spine fusion would have a risk profile similar to those who develop nosocomial infection. METHODS: We retrospectively analyzed records from patients with CP who developed infections after spinal fusion from January 1998 until July 2008, who were identified by our Infection Control Officer using National Nosocomial Infection Surveillance System criteria (N = 34). Demographically and procedurally matched controls without infection were identified from our spine database (N = 37). We compared these groups for gastroesophageal reflux disease (GERD), use of gastric acid inhibitors, presence of preoperative decubitus ulcer, previous infection, and postoperative ventilation. Multivariable logistic regression was then performed to assess the relative contributions of the predictors to "deep infection" and "any infection." RESULTS: Of 30 evaluable infected patients, 70% had incisional SSI. Although many of the infections were polymicrobial, the most common pathogens identified were Gram-negative bacilli. Many significant predictors were identified by univariable logistic regression for any infection and deep infection. Multivariable logistic regression found a significant effect only for GERD (odds ratio, 6.4; 95% confidence interval, 1.9-21.3; P = 0.002) for any infection, whereas the effect of therapy with gastric acid inhibitors did not reach statistical significance (odds ratio, 6.1 [95% confidence interval, 0.84-44.6]; P = 0.07). No significant interaction between the 2 factors was detected. Among our controls and infected patients altogether, 46.3% had GERD. CONCLUSIONS: We show that GERD increases the risk for infection in CP patients after spine fusion. Prospective multicenter studies are necessary to further validate the predictive value of this risk factor.

Suppressive and pro-inflammatory roles for IL-4 in the pathogenesis of experimental drug-induced liver injury.

The pathogenesis of immune-mediated drug-induced liver injury (DILI) following halogenated anesthetics, carbamazepine or alcohol has not been fully elucidated. Detecting cytochrome P450 2E1 (CYP2E1) IgG4 auto-antibodies in anesthetic DILI patients suggests a role for IL-4 in this hapten-mediated process. We investigated IL-4-mediated mechanisms using our model of experimental DILI induced by immunizing BALB/c (WT) and IL-4(-/-) (KO) mice with S100 liver proteins covalently modified by a trifluoroacetyl chloride (TFA) hapten formed following halogenated anesthetic metabolism by CYP2E1. WT mice developed more hepatitis, TFA and S100 antibodies (p<0.01), as well as T-cell proliferation to CYP2E1 and TFA (p<0.01) than KO mice. Additionally, WT CD4(+) T cells adoptively transferred hepatitis to naïve Rag(-/-) mice (p<0.01). Pro-inflammatory cytokines were expectedly decreased in TFA hapten-stimulated KO splenocyte supernatants (p<0.001); however, IL-2 and IFN-gamma (p<0.05), as well as IL-6 and IL-10 (p<0.001) levels were elevated in CYP2E1-stimulated KO splenocyte supernatants, suggesting dual IL-4-mediated pro-inflammatory and regulatory responses. Anti-IL-10 administered to KO mice increased hepatitis, TFA and CYP2E1 antibodies in KO mice confirming a critical role for IL-4. This is the first demonstration of dual roles for IL-4 in the pathogenesis of immune-mediated DILI by suppressing auto-antigen-induced regulatory responses while promoting hapten-induced pro-inflammatory responses.

Induction of Drug-Induced, Autoimmune Hepatitis in BALB/c Mice for the Study of Its Pathogenic Mechanisms.

Drug-induced autoimmune hepatitis (DIH) is the most common hepatic drug-induced hypersensitization process observed in approximately 9 to 12% of patients with autoimmune hepatitis. The overwhelming majority of patients with DIH are women. The underlying mechanisms of these sex differences in prevalence are unclear because of the paucity of animal models that mimic human disease. Even so, underlying mechanisms are widely believed to be associated with human leukocyte antigen haplotypes and sex hormones. In contrast, using a DIH mouse model, we have uncovered that IL-4 initiated CD4+ T cells directed against an epitope of cytochrome P450 2E1 induces influx of neutrophils, macrophages and mast cells into the livers of female BALB/c mice. Using this model, we have also shown that IL-33-induced FoxP3+regulatory T cells confer protection against DIH in female and male mice. This DIH model is induced by immunizing mice with an epitope of CYP2E1 that has been covalently altered with a drug metabolite that has been associated with DIH. This epitope is recognized by patients with DIH. Our method induces robust and reproducible hepatitis and autoantibodies that can be utilized to study the pathogenesis of DIH. While in vivo studies can cause undue pain and distress in mice when done improperly, the advantage of an in vivo model is the ability to evaluate the pathogenesis of disease in a large number of mice. Additionally, biological effects of the altered liver proteins can be studied using invasive procedures. The addition of in vitro studies to the experimental design allows rapid repetition and mechanistic analysis at a cellular level. Thus, we will demonstrate our model protocol and how it can be utilized to study in vivo and in vitro mechanisms of DIH.

Opioid prescribing practices after posterior spinal arthrodesis for adolescent idiopathic scoliosis.

STUDY DESIGN: Retrospective review. OBJECTIVE: To identify national trends in postoperative opioid prescribing practices after posterior spinal fusion (PSF) in patients with adolescent idiopathic scoliosis (AIS). Opioids are an important component of pain management after PSF for AIS. Given the national opioid crisis, it is important to understand opioid prescribing practices in these patients. METHODS: Using a commercial prescription drug claims database, we identified AIS patients who underwent PSF from 2010 to 2016 and who were prescribed opioids postoperatively. An initial prescription at hospital discharge of ≥ 90 morphine milligram equivalents daily (MMED) was used to identify patients at risk of overdose according to the US Centers for Disease Control and Prevention (CDC) guidelines. Prescriptions for skeletal muscle relaxants were also identified. α = 0.05. RESULTS: We included 3762 patients (75% female) with a mean (± standard deviation) age of 15 ± 2.1 years. 56% of patients filled only 1 opioid prescription after discharge, and 44% had ≥ 1 refills. 91% of opioid prescriptions were for hydrocodone (median strength, 43 MMED; mean strength, 65 ± 270 MMED) or oxycodone formulations (median strength, 60 MMED; mean strength, 79 ± 174 MMED). 82% of prescriptions complied with CDC guidelines (< 90 MMED). Overall, 612 patients (16%) filled ≥ 1 prescription for skeletal muscle relaxants, the most common being cyclobenzaprine (45%) and methocarbamol (29%). The percentage of patients filling > 1 prescription declined from 54% in 2010 to 31% in 2016 (p < 0.001). The proportion of patients receiving prescriptions for ≥ 90 MMED was highest in the West (29%) and lowest in the South (16%) (p < 0.001). CONCLUSION: Most opioid prescriptions after PSF in patients with AIS comply with CDC guidelines. Temporal and geographic variations show an opportunity for standardizing opioid prescribing practices in these patients. LEVEL OF EVIDENCE: III.

Correction to: Opioid prescribing practices after posterior spinal arthrodesis for adolescent idiopathic scoliosis.

The original version of this article unfortunately contained a mistake.

An Advanced Boot Camp for Pediatric Anesthesiology Fellows.

BACKGROUND: Managing pediatric crises necessitates the acquisition of unique skills and confidence in its execution. Our aim was to develop and assess a curriculum based on the constructivist learning environment to enhance learning, orientation, and preparation of graduating pediatric anesthesiology fellows. METHODS: Fifty pediatric anesthesiology fellows from 9 academic institutions in the United States were recruited for an advanced boot camp over a 2-year period. Training stations were developed using high-fidelity simulation, standardized patients, self-reflection modules, and facilitated discussions. The curriculum was evaluated using an anonymous survey that assessed knowledge, self-confidence, appropriateness of case-scenario complexity, and usefulness for transitioning into an independent practitioner on a Likert scale (1 = strongly disagree to 5 = strongly agree). Data points were expressed as the median and interquartile range (IQR). RESULTS: Ninety-eight percent of the fellows completed a survey. Fellow perceptions of the advanced boot camp was positive. The median scores (IQR) for knowledge, self-confidence, appropriateness of case complexity, and usefulness for transition in 2017 were 5 (3,5), 4.5 (3,5), 5 (3,5), and 5 (3,5), respectively, and 5 (3,5), 4.5 (3,5), 5 (4,5), and 5 (3,5), respectively, in 2018. The IQR in the assessment for an appropriate level of complexity for their level of training, narrowed in 2018 (4,5), when compared with 2017 (3,5). CONCLUSIONS: Fellow responses support the idea that the advanced boot camp provided tools and strategies for their transition. A narrowed IQR regarding the appropriate level of complexity of scenarios in 2018, when compared with 2017, might suggest an improvement in the curriculum.

In drug-induced, immune-mediated hepatitis, interleukin-33 reduces hepatitis and improves survival independently and as a consequence of FoxP3+ T-cell activity.

Immune-mediated, drug-induced hepatitis is a rare complication of halogenated volatile anesthetic administration. IL-4-regulated Th2-polarized reactions initiate this type and other types of hepatitis, while the mechanisms that regulate the severity remain elusive. IL-33 is an innate, IL-4-inducing, Th2-polarizing cytokine that has been detected in patients with liver failure and has been associated with upregulated ST2+Foxp3+CD4+CD25+ T cells; however, roles for IL-33 in drug-induced hepatitis are unclear. We investigated IL-33 in an anesthetic, immune-mediated hepatitis modeled in BALB/c, IL-33-/- and ST2-/- mice, as well as in patients with anesthetic hepatitis. The hepatic IL-33 and ST2 levels were elevated in BALB/c mice (p < 0.05) with hepatitis, and anti-IL-33 diminished hepatitis (p < 0.05) without reducing IL-33 levels. The complete absence of IL-33 reduced IL-10 (p < 0.05) and ST2+Foxp3+CD4+CD25+ T cells (p < 0.05), as well as reduced the overall survival (p < 0.05), suggesting suppressive roles for IL-33 in anesthetic, immune-mediated hepatitis. All of the mice demonstrated similar levels of CD4+ T-cell proliferation following direct T-cell receptor stimulation, but we detected splenic IL-33 and ST2-negative Foxp3+CD4+CD25+ T cells in ST2-/- mice that developed less hepatitis than BALB/c mice (p < 0.05), suggesting that ST2-negative Foxp3+CD4+CD25+ T cells reduced hepatitis. In patients, serum IL-33 and IPEX levels were correlated in controls (r2 = 0.5, p < 0.05), similar to the levels in mice, but not in anesthetic hepatitis patients (r2 = 0.01), who had elevated IL-33 (p < 0.001) and decreased IPEX (p < 0.01). Our results suggest that, in anesthetic, immune-mediated hepatitis, IL-33 does not regulate the CD4+ T-cell proliferation that initiates hepatitis, but IL-33, likely independent of ST2, reduces hepatitis via upregulation of Foxp3+CD4+CD25+ T cells. Further studies are needed to translate the role of IL-33 to human liver disease.

Identification of a Shared Cytochrome p4502E1 Epitope Found in Anesthetic Drug-Induced and Viral Hepatitis.

Cytochrome p4502E1 (CYP2E1) autoantibodies are biomarkers for drug-induced hepatitis and chronic hepatitis C. However, major histocompatibility-restricted CYP2E1 epitopes associated with these diseases have not been identified. We hypothesized that CYP2E1 epitopes associated with different types of hepatitis may be shared and may impact immune responses and metabolism. SYFPEITHI epitope prediction identified CYP2E1 candidate epitopes that would be recognized by MHC II haplotypes. Candidate epitopes were tested for induction of hepatitis and CYP2E1 autoantibodies in mice and recognition by sera from patients with anesthetic drug-induced and viral hepatitis. Human liver cells treated with epitope hybridoma serum were analyzed for mitochondrial stress. CYP2E1 activity was measured in human microsomes similarly treated. Epitope antibodies in viral hepatitis sera were analyzed using linear regression to uncover associations with liver pathology. A P value of <0.05 was considered significant. One epitope (Gly113-Leu135) induced hepatitis and CYP2E1 autoantibodies in mice after modification of Lys123 (P < 0.05). Gly113-Leu135 antiserum recognized mitochondria and endoplasmic reticula (P < 0.05), upregulated HSP27 (P < 0.01) and mitochondrial oxidative stress via complex 1 inhibition (P < 0.001), and inhibited CYP2E1 activity. Gly113-Leu135 IgG4 detected in viral hepatitis sera was associated with severe hepatic fibrosis (P = 0.0142). We found a novel CYP2E1 epitope that was detected in anesthetic and viral hepatitis and that triggered hepatitis in mice. Our findings may improve understanding of hepatic immune responses triggered by metabolism or viruses.IMPORTANCE Drug-induced hepatitis is the leading reason that an approved drug is removed from the commercial market. Halogenated anesthetics can induce hepatitis in susceptible persons, and cytochrome p4502E1 (CYP2E1) enzymes responsible for their metabolism induce antibodies in addition to hepatitis. CYP2E1 antibodies detected in anesthetic hepatitis patients have been detected in patients with viral hepatitis, suggesting that these different forms of hepatitis could develop immune reactions to a common segment or epitope of CYP2E1. We have found a common MHC-restricted CYP2E1 epitope in anesthetic and viral hepatitis that is a dominant epitope in anesthetic hepatitis and is significantly associated with fibrosis in patients with viral hepatitis. Along with conformational epitopes, our identification of MHC-restricted CYP2E1 epitopes can be used to develop specific diagnostic tests for drug-induced or viral hepatitis or associated fibrosis or to predict individuals at risk for developing these diseases or their sequelae.

Desflurane hepatitis associated with hapten and autoantigen-specific IgG4 antibodies.

BACKGROUND: Three cases of drug-induced liver injury (DILI) have been reported after desflurane anesthesia. However, no previous reports have detected serum autoantibodies such as that reported with DILI from halothane or isoflurane. METHODS AND RESULTS: We describe the first documentation of cytochrome P450 2E1 IgG4 autoantibodies, as well as 58 kDa endoplasmic reticulum protein and trifluoroacetyl chloride hapten-specific IgG4 antibodies, in a patient who developed DILI after desflurane anesthesia. CONCLUSIONS: These findings suggest that allergic and autoimmune mechanisms have critical roles in the development of desflurane DILI.