United States

Background
Gastrointestinal (GI) complaints are the most common categorical presentations in emergency departments (EDs), accounting for approximately 11% of all ED visits in the United States. Many of these GI emergencies do not involve a structural cause and are presumed to be disorders of the gut-brain interaction (DGBIs). DGBIs such as irritable bowel syndrome, functional constipation, and functional dyspepsia affect approximately 40% of the world’s population and pose a major public health concern. Despite this, little is known about patient characteristics, comorbidities, and outcomes of DGBIs in the ED setting. Consequently, many patients with DGBIs undergo repeat ED visits, testing, and opioid exposure, posing a strain on both the patient and the broader healthcare system. 

Methods
We conducted a prospective, multi-center observational cohort study at four U.S. hospitals, enrolling adults presenting to the ED who were determined by three independent physicians to have recurrent abdominal pain without clear structural etiology. Participants completed standardized surveys assessing pain severity, psychiatric symptoms, substance use, and social determinants of health. Chart review captured clinical management, diagnostic testing, and health care utilization at the index visit, and at 30 days and 12 months post-visit. 

Results
Analysis is ongoing, and preliminary results from George Washington University Hospital (GWUH) are provided. A total of 95 participants at GWUH were enrolled. The mean age was 36.29 years, 65.3% were female, and 69.5% identified as Black. Unmet social needs were frequently identified in finances (43.2%), food insecurity (37.9%), and housing (29.5%). Past medical history of anxiety and depression were found in 46.3% and 41.1% of study participants, respectively. Moderate- to high-risk cannabis use was present in 40.0% of the participants. Opioids were administered to 20.0% of eligible patients during their ED visit, and 3.2% were discharged with an opiate prescription. Thirty days following the index visit, 12.6% returned to the ED. At 12 months, 25.3% have had at least one additional ED visit.

Conclusions
Adults presenting to the ED with recurrent abdominal pain and no structural cause are predominantly young, female, and from minoritized populations. Comorbidities, including anxiety and depression, are common among eligible patients, as well as food insecurity and financial distress. Repeat ED visits, CT scans, and opioid prescriptions are frequent, yet structural causes are rarely identified. Many eligible patients additionally engage in moderate- to high-risk substance use, particularly with cannabis. Identification of key risk factors may inform targeted interventions to improve outcomes in patients experiencing DGBIs.

AMA Research Challenge 2025 

Unmasking the Mystery: Outcomes of Recurrent Abdominal Pain Without Structural Cause in U.S. Emergency Departments

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AMA Research Challenge 2023

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Background

Angiotensin-converting enzyme inhibitors (ACEI) are among the most prescribed class of antihypertensives worldwide. ACEIs influence carcinogenesis through suppression of vascular endothelial growth factor (VEGF), a key mediator of tumor angiogenesis. Animal models and in vitro studies show ACEIs inhibit tumor growth and angiogenesis independent of angiogenesis II type 1 receptor blockade, and reduced VEGF levels in tumor tissue. However, large-scale real-world evidence on site-specific cancer risks associated with ACEI use is limited. This study evaluated the association between ACEI use and incident solid tumors, including breast, colorectal, and lung cancers, in a large hypertensive population. 

Methods

This retrospective cohort study used the TriNetX Research Network, a global federated network of de-identified electronic health records from over 92 healthcare organizations, encompassing > 100 million patient charts (2003-2024). Adults aged ≥ 40 years with a history of hypertension and ≥ 2 prescriptions for an ACEI (exposure group) or a non-ACEI antihypertensive (control group) were included. The index event was the second prescription. Patients with prior cancer diagnoses were excluded. Outcomes were new diagnoses of solid tumors (ICD-10 C00-C80), breast cancer (C50), colorectal cancer (C18-C20), and lung cancer (C34) occurring ≥ 90 days post-index to reduce confounding. Propensity score matching (1:1) used 11 covariates, including age, sex, race/ethnicity, BMI, smoking, type 2 diabetes, and chronic kidney disease. Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs). 

Results

A total of 4,715,467 ACEI users and 6,363,948 non-ACEI users met inclusion criteria; after matching, 4,455,986 patients remained in each cohort. Breast cancer occurred in 51,069 ACEI users vs 43,255 non-ACEI users, colorectal cancer in 34,104 vs 26,037, and lung cancer in 56,484 vs 42,775. ACEI use was not associated with overall solid tumor risk (HR 1.005, 95% CI: 1-1.009), but breast cancer risk was reduced (HR 0.934, 95% CI: 0.922-0.946; p<0.0001), whereas colorectal cancer (HR 1.04, 95% CI: 1.024-1.057; p<0.0001), and lung cancer (HR 1.034, 95% CI: 1.021-1.047; p<0.0001) risks were significantly higher.

Conclusion

ACEI use was associated with site-specific cancer risks, suggesting tissue-dependent effects of renin-angiotensin system modulation. The protective breast cancer effect may reflect anti-angiogenic or estrogen-mediated mechanisms, whereas the increased colorectal and lung cancer risks may involve inflammatory or bradykinin-related pathways. These findings warrant mechanistic studies and may inform cancer surveillance strategies and antihypertensive prescribing decisions. Evaluating whether these associations differ by sex or race will be crucial for equitable screening recommendations.



ACE Inhibitors Show Site-Specific Cancer Risks: A Multi-Center Retrospective Study

Abstract Title 
Neurological Symptom Mapping for Acute Ischemic Stroke - A Novel Tool for Predicting Occlusion Location
Jean Bernard Salloum, Tarek Belhadad, Matthew Dinh, Rocky Rafi, Arshan Halkor, Ahmed Pasha, Dr. John Ashurst 

Background 
Timely stroke localization is critical for effective treatment; however, CTA—the current standard for identifying vessel occlusions—has accessibility and diagnostic limitations. Only 39% of frontier hospitals have 24-hour CT access, and over 20% of the population lives more than an hour from advanced stroke centers. Rural patients are half as likely to receive thrombolytics and one-third less likely to undergo thrombectomy than urban patients. Even with CTA available, renal impairment, patient stability, and motion artifacts limit efficacy. To address this, we developed a questionnaire with an embedded algorithm that translates overlooked 
clinical signs into stroke localization. As a non-imaging tool, our tool may support rapid diagnostic and treatment decisions when CTA is delayed or inconclusive. 

Methods 
To construct a clinically grounded model for ischemic stroke localization, we integrated major neurovascular territories, clinical syndromes, and symptoms into a stroke database. Validation was performed using reputable medical textbooks corroborated with data from peer-reviewed literature. This provided a framework to program our software - encoded with a structured clinical questionnaire and algorithm that predicts ischemic stroke locations. 

To evaluate accuracy of the algorithm, we curated a validation dataset from published peer reviewed case reports (2000–present). Inclusion criteria for cases required documentation of at least two focal neurological signs and confirmatory imaging findings (CT or MRI). 

We implemented a triple-blind protocol for testing to minimize bias: 
• Researcher A extracted clinical data and imaging results from reports. 
• Researcher B entered anonymized clinical data into the algorithm. 
• Researcher C analyzed algorithm predicted stroke locations as compared to imaging confirmed locations.

Results 
The stroke database included 21 ischemic strokes with characteristic symptomology. We identified 103 potential case reports for algorithm testing, of which 77 met inclusion criteria. 
Regarding major vessel territories, such as the MCA, ACA, PCA, ICA and Basilar Artery, the model demonstrated an average sensitivity of 97.0% and specificity of 78.6%. For each of their respective sub-branches, an average sensitivity of 87.0% and specificity of 90.3% was achieved. Of note, lacunar infarcts showed a sensitivity of 100% and specificity of 90.9%.

Conclusion 
Our model demonstrated high sensitivity for major vessel strokes and strong specificity for sub-branch level infarcts. Notably, it accurately detected deep, diagnostically challenging infarcts such as brainstem or lacunar strokes with consistent reliability. These findings support the model's potential to enable early and accurate stroke localization using physical exam findings, which may assist in triage and initiating treatment in settings with limited imaging access or ambiguous 
findings.

Neurological Symptom Mapping for Acute Ischemic Stroke - A Novel Tool for Predicting Occlusion Location

Background
Preterm labor is the leading cause of infant mortality and morbidity worldwide, yet no pharmacological treatments currently exist to combat it. Although potentially effective therapies exist to suppress undesirable uterine contractions, these drugs often transport across the placental barrier, leading to adverse consequences on the developing fetus. Formulation strategies to limit fetal exposure may enable the safe and effective use of currently approved drugs for the prevention of preterm birth. Poly(lactic-co-glycolic) acid (PLGA) is a biocompatible copolymer that is used in a variety of drug formulations and in ‘dissolvable’ sutures. We hypothesize that optimally sized PLGA particles formulated with an anti-tocolytic will limit placental transport and suppress uterine contractions.
Methods
Therefore, we synthesized PLGA particles loaded with cargo and tested two formulations via an oil-in-water emulsion fabrication technique. One formulation used dichloromethane (DCM) with polyvinyl alcohol (PVA), and the other used ethyl acetate (EtAc) with D-α-tocopheryl polyethylene glycol succinate (Vitamin E-TPGS); both have been reported to successfully prepare PLGA particles in the target diameter range. Further studies to prove model translatability were performed, including kinetic release using two common tocolytics (indomethacin and nifedipine), in-vivo biodistribution, and ex-vivo experiments using murine uterine strips.
Results
The resulting EtAc/Vit E-TPGS emulsion produced average particle diameters of 1350 (± 64.5) nm (PDI: 0.3037). However, this formulation was more polydisperse compared to the DCM/PVA emulsion with average particle diameters of 1251 (±300.4) nm (PDI: 0.2020) that also exhibited acceptable day-to-day variability, ranging from 1137 to 1734 nm. We showed successful drug encapsulation in the absence of variation in particle size for indomethacin 1267 (± 82.72) nm and nifedipine 1142 (± 1.155) nm. Both tocolytics show the capacity for sustained release with total cumulative release of indomethacin (30 days) and nifedipine (24 days). In-vivo biodistribution studies demonstrate localization of the targeted PLGA particles to the uterus, and ex-vivo studies present a clear effect of the tocolytic drug after loading. 
Conclusion
Through optimized physiochemical characteristics and clinical translation, this formulation has the potential to effectively inhibit preterm labor contractions in a novel delivery system. Next steps include decoration of particles with a uterine-selective antibody corona. The function of drug-loaded PLGA particles to inhibit uterine contractions will be tested in a model system with human tissue in organ baths. Results of these studies will be used to refine the drug to PLGA ratio and the PLGA characteristics to optimize efficacy and toxicity.

Developing a Nanoparticle Drug Delivery System to Treat Preterm Labor

Background
The use of low-dose colchicine in the orthopedic treatment of non-crystalline arthropathy conditions is not well-explored. Colchicine is an antimitotic drug that inhibits neutrophils and has demonstrated anti-inflammatory properties. Colchicine lacks many of the adverse effects associated with Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), including upper gastrointestinal bleeding, nephrotoxicity, and hypertension exacerbation. This study evaluates the safety and effectiveness of low-dose colchicine as an alternative to NSAIDs in the conservative treatment of orthopedic patients.

Methods
A retrospective chart review was conducted at a single orthopedic clinic from March 2024 to February 2025. Patients treated for orthopedic conditions with colchicine 0.6 mg orally once daily, who had patient-reported Visual Analog Scale (VAS) pain scores recorded at the initial and first follow-up visit, were included. Patients with crystalline arthropathies were excluded. Descriptive analyses were performed to assess the mean and standard deviation of VAS-pain scores before and after treatment. A subgroup analysis was performed after excluding patients who received procedures or injections at the initial visit to evaluate the impact of this confounding variable.

Results
Of 306 patients reviewed, 144 met the inclusion criteria. The mean age was 62.93 ± 14.21 years (101 females, 43 males), with an average follow-up of 56.21 ± 35.82 days. The mean VAS-pain scores at the initial and first follow-up visit were 6.76 ± 2.33 and 5.35 ± 2.88, respectively. The mean reduction in pain (follow-up - initial) was -1.42 ± 3.02. Two patients reported side effects, including joint pain and gastrointestinal symptoms. No serious adverse events were reported. After excluding patients who had procedures or injections (n = 117), the mean VAS-pain scores were 6.53 ± 2.40 initially and 5.35 ± 2.99 at follow-up. The mean reduction in pain for this group was -1.18 ± 3.08.

Conclusion
These results suggest that low-dose colchicine may represent a safe alternative to NSAIDs in the conservative treatment of orthopedic patients. While a modest reduction in pain scores was observed, further controlled studies with larger cohorts and longer follow-up are needed to determine efficacy and statistical significance.


Low-Dose Colchicine as an NSAID Alternative in Orthopedic Patients: A Retrospective Review


Background: Perioperative opioid prescriptions have been shown to increase the risk of persistent opioid use in opioid-naive patients undergoing gastrointestinal surgery. However, there remains a lack of literature that evaluates whether national opioid prescribing trends and opioid-related outcomes may differ with more minimally invasive gastrointestinal surgeries as stratified through the endoscopic and laparoscopic approaches. This study evaluates the association between perioperative opioid use and persistent opioid use in opioid naïve patients receiving minimally invasive gastrointestinal surgeries involving either an endoscopic or laparoscopic approach. 

Methods: We conducted a retrospective cohort studying using data from the TriNetX US Collaborative network, including 3.2 million opioid-naive patients undergoing GI procedures from 2016 to 2024. Patients with a perioperative opioid prescription, as defined by an opioid prescription ranging from 1 month prior to surgery to 3 days after surgery, were propensity score-matched 1:1 to controls. Our primary outcomes were persistent opioid use within 30 days and 180 days postoperatively. 

Results: The incidence of opioid use has decreased. A perioperative opioid prescription was significantly associated with increased opioid use within 30 days across all surgical approaches: endoscopic and laparoscopic. Periopeapersistent opioid use, emergency department visits, opioid overdose, opioid dependence, and all-cause mortality

Conclusions: Perioperative opioid prescriptions are strongly associated with persistent opioid use at both 1 and 6 months after endoscopic and laparoscopic GI surgery. In endoscopic cases, opioids were also linked to higher risks of overdose, dependence, ED visits, hospitalizations, and mortality. Laparoscopic patients showed a more nuanced risk profile—persistent opioid use was consistently higher, but secondary outcomes varied, with some evidence of reduced inpatient stays and mortality. These findings highlight the need for procedure-specific opioid stewardship strategies to minimize harm while ensuring adequate pain control.


Evaluation of National Opioid Prescribing Trends and Outcomes in Gastrointestinal Surgery- Endoscopic and Laparoscopic Approaches

Attention-deficit hyperactivity disorder (ADHD) is the most common neurocognitive disorder diagnosed in children, with an estimation of six million children aged 3-17 diagnosed with ADHD. Stimulants are the first-line treatment for children with ADHD but may cause adverse effects. This study aims to shed light on non-pharmacological approaches to treating children with ADHD, specifically exercise and dietary modifications. This literature-based review evaluated current research on PubMed focusing on the impact of exercise and dietary modifications as forms of treatment for ADHD. Though studies differ on what symptoms are most improved, exercise was found to be cost-effective and beneficial in ADHD symptom management. Of note, hyperactivity and aggressive behavior improved in children with ADHD after a yoga regimen was implemented in one study. In addition to exercise, the literature review found that a healthy diet consisting of vegetables and fish is the recommended choice for aiding in ADHD symptom management. Omega-3, zinc, iron supplementations, and dietary interventions such as few foods diet (FFD) and a polyunsaturated fatty acids (PUFA) diet, are not recommended due to inconsistent effects on reducing symptoms.

Effective Non-Pharmacological Options for Managing ADHD in the Pediatric Population

Background
->Chronic Thromboembolic Pulmonary Hypertension (CTEPH) is a severe complication of pulmonary embolism (PE) characterized by by non-resolving thrombi and progressive vascular remodeling that fails to resolve and transforms into fibrotic tissue, permanently occluding pulmonary arteries.
->While inflammation is implicated, the role of specific immune cells, particularly monocyte subsets, in thrombus persistence is unclear.

Introduction
Monocytes act as immune gatekeepers, and the disrupted coordination of these subsets impairs thrombus resolution and establishes an immune–fibrotic niche, a hallmark of CTEPH.
They exist as three major subsets:
-Classical monocytes (CM; CD14⁺⁺CD16⁻)
-> Inflammatory and rapidly recruited to sites of injury. 
-> Cells rely on C-C Chemokine Receptor Type 2 (CCR2), which enables their mobilization from the bone marrow into the bloodstream.
-Intermediate monocytes (Int-M; CD14⁺⁺CD16⁺) 
-> Transitional state between CM and NCM.
-> Act as a Potent antigen presentation and secrete inflammatory cytokines (TNF-α, IL-1β, IL-10)
-Non-classical monocytes (NCM; CD14⁺CD16⁺⁺) 
-> Patrol the endothelium and are involved in tissue repair and remodeling.
-> Their development depends on the transcription factor Nuclear Receptor Subfamily 4 Group A Member 1 (NR4A1).
We employed a partial inferior vena cava (IVC) ligation model in mice to mimic thrombosis with incomplete resolution leading to fibrotic residual clot, analogous to human CTEPH for translational implications(Fig.1).
For translational validation, we analyzed human PTE specimens and peripheral blood from CTEPH patients(Fig.2).

Methods
In the Murine model:
A Partial Inferior vena cava ligation was performed in Wild-type C57BL(B6)and genetic knockouts(KO) lacking CM(CCR2KO), and the absence of NCM (NR4A1KO) mice. Thrombi and IVC wall were harvested at acute (Days 1–2), subacute (Day 7), and chronic (Day 14) timepoints to assess weight(mg), length(mm), and vein-wall fibrosis via Masson’s trichrome (% collagen).
Human CTEPH Patients:
-Spatial transcriptomics (ST) using the 10x Xenium platform was conducted on:
- > 3 CTEPH tissue sections from pulmonary thromboendarterectomy(PTE).
->2 healthy pulmonary artery (PA) tissues from donor lungs
-Peripheral blood monocytes were isolated from 20 CTEPH patients with PTE and 10 controls.
->CM, INT-M, and NCM were sorted and quantified via flow cytometry.
->Bulk RNA sequencing was performed on classical monocytes to identify differentially expressed genes (DEGs) and pathways. 

Results
-In mice, both CCR2KO (CM-deficient) and NR4A1KO (NCM-deficient) mice exhibited accelerated thrombus formation and impaired resolution compared with B6(WT) controls (Fig.3A). 
-Thrombus weight remained elevated through Day 14 (CCR2KO vs B6, p = 0.02; NR4A1KO vs B6, p = 0.005), with only 33–47% resolution vs ~60% in B6 (Fig.3A).
Thrombus length decreased faster in KOs, reflecting compaction without degradation (Fig.3B).
-Histology showed a 1.8-fold increase in collagen deposition in NR4A1KO mice at Day 14 (p < 0.001), identifying NCMs as antifibrotic regulators of late thrombus remodeling.(Fig.4).
-Two-way ANOVA confirmed significant genotype (p = 0.028), time (p < 0.0001), and interaction (p < 0.0001)effects.
-In human CTEPH, spatial transcriptomics and RNA-seq revealed a monocyte-enriched fibrotic microenvironment composed of monocytes, macrophages, fibroblasts, and endothelial cells.
-Classical monocytes displayed >2,000 DEGs, including CTSG, MS4A3, FOXI2,AREG, denoting pro-inflammatory and profibrotic activation.
-Spatial mapping localized these monocytes within fibroblast-macrophage “Niche 5”, expressing MKI67, PCNA, CD68, CD83, linking circulating CM activation to vascular fibroblast proliferation.
-Endothelial subclusters (angiogenic, contractile, homeostatic) further supported remodeling and vascular stiffening in CTEPH lesions.
Cross-Species Integration
-Murine KO models recapitulate human CTEPH pathology: loss of CCR2⁺ CMs impairs thrombus clearance, while loss of NR4A1⁺ NCMs augments fibrosis.
-Human data mirror this imbalance, showing hyperactivated classical monocytes and loss of reparative signatures, together establishing a shared immune–fibrotic program that drives persistent thrombus remodeling.

Conclusion
-Loss of NR4A1⁺ non-classical monocytes removes an antifibrotic brake, allowing CCR2⁺ classical monocytes to dominate and orchestrate fibroblast–endothelial crosstalk—positioning classical monocytes as the key profibrotic effector in CTEPH.
-Hyperactivated classical monocytes (CD14⁺⁺CD16⁻) upregulate profibrotic genes (CTSG, MS4A3, AREG, FOXI2, PDGFRA, THBS2), driving fibroblast proliferation and endothelial remodeling—establishing CMs as the central effectors of fibrosis in CTEPH.
-A dual-target strategy targeting the CCR2⁺ classical monocyte axis and restoring NR4A1-mediated reparative signaling could rebalance immune–fibrotic responses and halt CTEPH progression and promote thrombus resolution.
-Combined inhibition of monocyte recruitment (CCR2) and fibroblast activation represents a rational immune-modulatory approach for future trials.


Monocyte Subset Reprogramming Drives Fibrosis in CTEPH: A Pathway to Immune-Targeted Therapy



Background:
Bioprosthetic valve degeneration, particularly involving the Trifecta surgical aortic valve, has become an increasingly recognized clinical challenge due to its propensity for early structural valve deterioration and failure. Severe aortic regurgitation (AR) resulting from immobile or flail valve leaflets often presents with complex hemodynamic consequences, including functional mitral stenosis—a condition also known as pseudo-mitral stenosis. This phenomenon occurs when the regurgitant aortic jet impinges upon the anterior mitral leaflet, restricting its motion and creating an obstruction to diastolic mitral inflow. Clinically, this manifests as an Austin Flint murmur and may mimic organic mitral valve disease, complicating diagnosis. Distinguishing functional mitral stenosis from intrinsic mitral pathology is critical because the treatment focus should be on correcting the primary aortic valve lesion. Valve-in-valve transcatheter aortic valve replacement (ViV-TAVR) has emerged as a less invasive, effective alternative to redo surgical valve replacement in patients with degenerated bioprosthetic valves who are at elevated surgical risk.
Case Presentation:
We report the case of an 84-year-old male with a history of a Trifecta bioprosthetic aortic valve replacement who presented with progressive exertional dyspnea, orthopnea, and acute hypoxic respiratory failure. Initial transthoracic and transesophageal echocardiography revealed severe eccentric AR due to an immobile bioprosthetic leaflet, accompanied by severe functional mitral stenosis characterized by a markedly elevated mean mitral valve gradient of 17 mmHg and reduced mitral valve area, despite structurally normal mitral leaflets. Right and left heart catheterization demonstrated elevated left atrial and pulmonary pressures, consistent with the dual-valve pathology. The patient’s comorbidities—including chronic kidney disease, severe obstructive sleep apnea, prior cerebrovascular accident with residual deficits, and frailty—rendered him high-risk for conventional redo surgery. After multidisciplinary evaluation, the patient underwent a transfemoral ViV-TAVR using a 23 mm Edwards SAPIEN Ultra valve with prophylactic coronary protection. Post-procedure imaging confirmed successful valve deployment with complete resolution of aortic regurgitation and significant reduction in mitral valve gradient to 6 mmHg. Mitral valve mobility and effective valve area improved, demonstrating reversal of functional mitral stenosis.
Discussion:
This case highlights the intricate pathophysiology of functional mitral stenosis secondary to severe AR caused by bioprosthetic valve degeneration. The findings underscore the importance of thorough echocardiographic and hemodynamic evaluation to differentiate pseudo-mitral stenosis from primary mitral valve disease. Correction of the aortic valve pathology alone can restore mitral valve function, obviating the need for direct mitral intervention. ViV-TAVR offers a safe and effective minimally invasive treatment option for high-risk patients with complex dual-valve dysfunction. Comprehensive pre-procedural imaging, including transthoracic and transesophageal echocardiography and computed tomography, is essential for accurate diagnosis and procedural planning, especially to mitigate risks such as coronary obstruction. This case adds to the growing evidence supporting ViV-TAVR in managing complex valvular heart disease and emphasizes the clinical relevance of recognizing the Austin Flint phenomenon in patients with severe aortic insufficiency.



Double Trouble, One Solution: Valve-in-Valve TAVR Corrects Both Aortic and Mitral Valve in a Complex Dual-Valve Pathology

Drug-Induced Liver Injury (DILI) often has delayed identification due to the latency and idiosyncratic nature of the injury. The treatment for DILI is removal of the offending agent and supportive care with consideration that ALT and AST can downtrend quickly whereas Alkaline Phosphatase may increase for months after. 
Our patient is a 22 year old male who presents with 5 days of abdominal pain and diarrhea accompanied by pale stools, dark urine, generalized pruritus, and scleral icterus. His liver enzymes were all elevated, and his R score was 2.2 suggestive of a mixed pattern of both hepatocellular and cholestatic liver injury. Initial workup tested for viral hepatitis, Wilson’s disease, alpha-1 antitrypsin deficiency, and hereditary hemochromatosis. The patient denied any new medications, supplements, or drug use other than natural cannabinoids. An autoimmune liver panel ruled out PBC/PSC, and Stool Studies were unrevealing for acute GI illness. The patient was sexually active with multiple partners, but STI work-up only showed a resolved syphilis infection.
Despite this negative laboratory work up, abdominal ultrasound revealed coarse echogenicity suggestive of hepatic inflammation and MRCP was significant for mild hepatomegaly. Finally, liver biopsy revealed mixed inflammatory infiltrate reflecting a likely drug-induced liver injury. Upon more thorough medical reconciliation, dispense reports from an out-of-city urgent care showed amoxicillin prescribed 2 months prior, and the patient ultimately revealed a history of strep throat treated with a full course of antibiotics which he had forgotten about. 
The patient’s presentation was consistent with this diagnosis but history and labs were originally unrevealing as the injury occurred months prior and symptoms manifested separately. This case demonstrates the importance of obtaining a detailed medication history and inquiring into older infections, as DILI can have a delayed presentation several months after the offending agent is removed and patients often do not recall certain medications until specifically prompted. It also exhibits the relative utility of liver biopsy in diagnosing otherwise vague presentations when noninvasive workup is inconclusive. This patient’s ALT and AST downtrended over time, but his Alkaline Phosphatase continued to increase even months after amoxicillin use. This variability in liver enzyme trends is due to cholestatic injury having a more protracted course because bile duct injury takes months to heal whereas hepatocellular injury can resolve within days.

Diagnostic Challenges of Amoxicillin Induced Liver Injury

Background: Pathogenic variants in SCN2A, a gene encoding the voltage-gated sodium channel (Nav1.2), contribute to a spectrum of epilepsy and neurodevelopmental disorders. The recurrent 16p11.2 duplication is a copy number variant risk loci commonly associated with developmental delays affecting speech and motor functions, with increased seizure risk. 

Case Description: Following a normal pregnancy, neonatal and early developmental period, this female patient was noted to have delayed developmental milestones and failure to thrive at 8 months of age. By 19 months of age, she began experiencing both focal and generalized seizures occurring up to 4 times daily over a 2-month period, ultimately leading to hospitalization. An EEG performed at this time demonstrated epileptiform discharges in the right central, right temporal, and left temporal head regions. Antiepileptic therapies were initiated, with lack of response to phenobarbital and oxcarbazepine, with intolerable side effects to lacosamide. At 20 months of age, regression of skills with worsening language and motor delays and recurrent hand flapping, prompted a titration of previous medications and initiation of clobazam. A brain MRI at this time demonstrated delayed myelination for age without other notable findings. Exam findings at this time included round hypotonic facies, coarse facial features, hypertelorism, arched eyebrows and long eyelashes. 

Results: Seizures persisted and were pharmacoresistant in nature, thus exome sequencing with concurrent chromosomal microarray analysis were initiated at age 20-months. Testing resulted with an interstitial duplication of 565kb of DNA at 16p11.2 (29635211_30199713)x3 and a pathogenic variant in SCN2A c.2557C>T (R853W).
The patient is now 3-years-old and continues to experience focal seizures, reflux, global developmental delay, and self-injurious behavior. A repeat brain MRI revealed progressive volume loss within the supratentorial brain. 

Discussion: This is the first reported case of patient with co-occurring16p11.2 duplication and a heterozygous SCN2A pathogenic variant. It is suspected that much of this patient’s phenotype is caused by the SCN2A variant. As a neurodevelopmental risk loci, the 16p11.2 duplication may increase this patient’s risk for more severe developmental delays, autism, or additional seizures types. Seizure control and early intervention therapies continue to be the mainstays of intervention to improve developmental outcomes, as to date there are no targeted anti-epileptic medications or other precision therapies for SCN2A-DEE.


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