The Suitability of Using the Ferret as a Model Organism in Biomedical Research

This paper reviews the literature data considering the use of the ferret as a model organism in biomedical research. The albino ferret is the most used variant from the ferret species as an animal model in biomedi-cal research. Its use as a pet is also known. Similarities have been identified between ferrets and humans in terms of the physiology and morphology of the respi-ratory system, but also on the pathogenesis or evolu-tion of some diseases on other organs and systems. Ferrets are intensively used in the study of respiratory diseases of viral nature, such as influenza and SARS-CoV, in hypersecretory respiratory disorders, such as cystic fibrosis, in the neuroendocrinology and neuro-anatomy, and even in gastric ulcer research. Through genetic engineering, transgenic ferrets have been ob-tained, such individuals reproducing the studied pa-thology much more faithfully.

Hyperammonemia is a risk factor for poor outcomes in patients with COVID-19.

Objective. We analyzed clinical features and laboratory markers of COVID-19 patients according to favorable outcomes versus fatal outcomes. Material and methods. The medical history of 80 patients was analyzed: 51 patients with favorable outcomes were included in group 1, 29 patients with a fatal outcome were included in group 2. Demographic data, duration of the disease, comorbid-ities, laboratory markers, and results of the instrumental studies were included. The ammonia level in the peripheral blood was de-termined by the express method using a PocketChem BA 4140 photometric portable analyzer. Results. Patients in group 2 were older (68+/-11 years) had hypertension stage 3 with high cardiovascular risk;every third had a history of myocardial infarction. At admission, patients from group 2 were most likely with febrile fever and high levels of inflammatory markers - predictors of a cytokine release syndrome. In addition, 71% of patients at admission had elevated ammonia levels. Hyperammonemia correlated with high ferritin levels, leukopenia, non-alcoholic fatty liver disease in patients, and lethal outcomes. Conclusions. The risks of poor COVID-19 outcomes are higher in comorbid patients of the older age group. Hyperammonemia may be one of the predictors of poor COVID-19 outcomes.Copyright © 2022, Media Sphera Publishing Group. All rights reserved.

Neuropsychiatric Sequelae of Hyperammonemia: Clinical Pearls for the CL Psychiatrist

Background/Significance: Hyperammonemia is known to cause acute and chronic neurotoxicity, and one of the most well-known clinical sequelae of hyperammonemia is encephalopathy (Ali, 2022). Valproic acid (VPA) has often been associated with inducing hyperammonemia (Baddour, 2018). Discussant will review a case of a patient with altered metal status and elevated ammonia level. Literature review will cover current literature on non-hepatic hyperammonemia, clinical grading of hepatic encephalopathy, and treatment options. Case: A 74-year-old male with schizoaffective disorder, bipolar type, and past medical history of CKD stage III and COVID-19 associated cognitive sequelae was being evaluated for behavioral dysregulation and psychosis attributed to acute psychiatric decompensation. Home medications included benztropine, aripiprazole tabs with aripiprazole long-acting injectable as well as VPA. After confirming medication adherence and obtaining a sub-therapeutic VPA level of 44 mcg/mL on admission, the VPA dose was increased from 1500mg qhs to 1750 mg qhs to manage agitation. After initial improvement, the patient developed lethargy with altered sensorium and inattention. Work-up revealed a VPA level of 106 mcg/mL, prompting discontinuation of VPA. Additionally, labs showed an ammonia level of 38 mumol/L, which increased to 51mumol/L a few days later. Discussion(s): While encephalopathy resulting from hepatic failure is well studied, there are fewer studies on the approach to and neuropsychiatric sequelae of non-hepatic hyperammonemia, often with varied reference values. The differential diagnosis for non-hepatic causes of hyperammonemia is broad, most notable for VPA, as well as carbamazepine and inborn errors of metabolism (Kalra, 2020). Additionally, there have been case reports on the interaction between VPA and other antipsychotics such as risperidone, which may be associated with an increased risk of hyperammonemia (Davoudi-Monfared, 2019). However, guidance is limited on evaluating asymptomatic versus symptomatic hyperammonemia. Treatment options include addressing underlying etiology as well as management of active symptoms. Conclusion/Implications: Given the neurotoxic effects of ammonia, it is important for the Consultation-Liaison Psychiatrist to consider non-hepatic hyperammonemia as an etiology of altered mental status, especially considering the effects of medications such as VPA. Further research on the clinical presentation of non-hepatic hyperammonemia and the longitudinal effects of hyperammonemia is necessary to determine the role of trending elevated values. References: Davoudi-Monfared, E., Radmehr, M., Ghaeli, P., & Mousavi, M. (2019). A Case Series of Severe Hyperammonemia Encephalopathy Related to Valproate: Can Antipsychotics Increase the Risk?. Iranian journal of psychiatry, 14(3), 248-252. Kalra A, Norvell JP: Cause for confusion: noncirrhotic hyperammonemic encephalopathy. Clin Liver Dis (Hoboken). 2020, 15:223-7. Ali R, Nagalli S. Hyperammonemia. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing;2022 Jan-. Available from: Baddour, E., Tewksbury, A., & Stauner, N. (2018). Valproic acid-induced hyperammonemia: Incidence, clinical significance, and treatment management. The mental health clinician, 8(2), 73-77. Copyright © 2022

Accidental prolonged aerosol exposure to 1.5% glycine solution via inhalation

Background: Glycine is an endogenous, non-essential, simple amino acid produced in the human body. A 1.5% solution is commonly used for irrigation in gynecologic and urologic procedures as it is a sterile, clear, non-irritating liquid. It is neutral, mildly acidic and nonpyrogenic, and as it is produced by the human body it does not cause allergic reactions. If an excessive amount is absorbed during a procedure it can result in electrolyte abnormalities, such as hyponatremia or hypocalcemia. It can also result in transient vision disturbances, changes in heart rate, hypotension, hyperammonemia, or encephalopathy. Glycine has been used as a diluent in certain inhaled therapies for COVID-19 infections, such as epoprostenol. We describe a case where a 1.5% glycine solution was inadvertently used for humidified oxygen via high flow nasal cannula as opposed to distilled water. Case report: The patient was a 70-year-old male who was admitted to the hospital for hypoxia related to a COVID-19 infection with O2 saturations in the 70-80% range. He was placed on high flow nasal cannula to improve his oxygen levels. During his inpatient stay it was discovered that a 3-L bag of 1.5% glycine solution had been connected to the high flow nasal cannula instead of distilled water. This ran from Friday evening to the following Monday morning before the error was discovered. There was only 100mL of the glycine solution remaining in the bag when it was found. The patient continued to do well and had no new complaints during his stay. The case was called to the regional poison center which recommended monitoring electrolytes, watching for any possible respiratory symptoms and continuing supportive care. Initial lab work on admission showed a chemistry panel of Na 146, K 3.6, Cl 102, CO2 25.3, BUN 9, Cr 0.70, Glucose 106, Ca 9.3. Repeat lab work immediately after the mistake was found showed: Na 137, K 4.8 Cl 100, CO2 28, BUN 15, Cr 0.70, Glucose 129, Ca 9.0. On recommendations from poison control, electrolytes were monitored with repeat lab work 10 h after discontinuation of the glycine solution, showing: Na 135, K 4.3, Cl 97, CO2 26.8, Glucose 175, Ca 9.2. The patient did not develop any new complaints, had no reported altered mental status, epistaxis, nasal irritation or other symptoms related to the inhalation. He was eventually discharged home on oxygen for his persistent hypoxia related to his COVID-19 lung infection. Discussion(s): This case demonstrates that prolonged continuous inhalational exposure to a 1.5% glycine irrigation solution does not result in any mucosal irritation, metabolic or systemic toxic reactions, even though its pH is reportedly between 4.5 and 6.5. Thus, glycine solutions up to this concentration appear to be safely tolerated for its increasing use as an excipient for aerosolized medications. Conclusion(s): We describe a case where 1.5% glycine solution was inadvertently used in place of distilled water for humidified oxygen via high flow nasal cannula for approximately 3 days in a patient being treated for COVID-19 related pneumonia with no notable adverse effects.

HYPERAMMONEMIA POSTLUNG TRANSPLANTATION: AN UNCOMMON BUT LIFE-THREATENING COMPLICATION

SESSION TITLE: Lung Transplantation Cases SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/18/2022 10:15 am - 11:10 am INTRODUCTION: Hyperammonemia is an uncommon yet serious complication that has been described in patients after solid organ transplantation, most commonly after lung transplantation. It has an incidence of about 2-4 % and a high fatality rate. Given the myriad of etiologies that can lead to encephalopathy post lung transplantation, hyperammonemia can easily be missed unless we have a high index of suspicion. Unlike in hepatic cirrhosis, non cirrhotic hyperammonemia can result in rapidly rising high levels of ammonia which can result in cerebral edema, seizures and long term neurological deficits. Hence, quick diagnosis and a multi faceted treatment approach is required for a favorable outcome CASE PRESENTATION: 37 year old man with COVID pneumonia and respiratory failure on ECMO support underwent bilateral orthotopic lung transplant. He had no significant past medical history. ECMO was decannulated on post op day 4 and by day 6 he was progressing well and working with physical therapy. On post op day 11 he had an abrupt decline in mental status and had an episode of seizure. Initial ammonia level was 181 uMol/L (Normal < 45 uMol/L) with a peak level of 248 uMol/L. Bronchial wash was positive for Ureaplasma species by PCR. CT head did not reveal any signs of cerebral edema. Management included daily hemodialysis, Sodium phenyl butyrate, Levocarnitine, Rifaximin, Lactulose and Doxycycline. Mental status started improving and ammonia levels normalized in the next 4 days. He was subsequently discharged home from the hospital without any neurological deficits. DISCUSSION: The etiology of post lung transplant hyperammonemia is not very clear. The etiology with the most evidence is an infection with urease producing bacteria as in our patient. Based on this, obtaining a PCR screening for these organisms in the Donor/recipient has been proposed. Obtaining a screening ammonia level at around day 7 post transplant has also been suggested. Given the high mortality and morbidity associated with this condition an aggressive multimodal treatment approach is required that includes renal replacement therapy, Nitrogen scavengers, bowel decontamination and empiric antibiotics. Hemodialysis has been shown to be more effective than continuous veno-venous hemodialysis for ammonia clearance. Antibiotics such as Azithromycin and Doxycycline that would be effective against urease producing organisms should be administered. In patients with signs of raised intracranial pressure, prompt neuroimaging and also measures to reduce cerebral edema must be instituted. CONCLUSIONS: Clinical signs of hyperammonemia should be promptly recognized in post lung transplant patients and managed aggressively given high mortality rates without treatment. A multi-pronged treatment approach with Intermittent high flux hemodialysis, bowel decontamination and agents targeting the urea cycle should be used to rapidly decrease the ammonia levels. Reference #1: Krutsinger D, Pezzulo A, Blevins AE, Reed RM, Voigt MD, Eberlein M. Idiopathic hyperammonemia after solid organ transplantation: Primarily a lung problem? A single-center experience and systematic review. Clin Transplant. 2017 May;31(5). doi: 10.1111/ctr.12957. Epub 2017 Apr 7. PMID: 28295601. Reference #2: Leger RF, Silverman MS, Hauck ES, Guvakova KD. Hyperammonemia Post Lung Transplantation: A Review. Clin Med Insights Circ Respir Pulm Med. 2020 Oct 26;14:1179548420966234. doi: 10.1177/1179548420966234. PMID: 33192115;PMCID: PMC7594252. Reference #3: Anwar S, Gupta D, Ashraf MA, Khalid SA, Rizvi SM, Miller BW, Brennan DC. Symptomatic hyperammonemia after lung transplantation: lessons learnt. Hemodial Int. 2014 Jan;18(1):185-91. doi: 10.1111/hdi.12088. Epub 2013 Sep 2. PMID: 23998793. DISCLOSURES: Research Grant relationship with Alung Please note: $1001 - $5000 by Bindu Akkanti, value=Grant/Research Support No relevant relationships by Soma Jyothula no disclosure on file for Manish Patel;No relevant relationships by Sandeep Patri

Safety Profile of Tyrosine Kinase Inhibitors Approved for Gastrointestinal Stromal Tumors: Analysis from the European Spontaneous Adverse Event Reporting System: An International Journal of Medical Toxicology and Drug Experience

Introduction: Gastrointestinal stromal tumors (GISTs), soft tissue sarcomas of the digestive tract, are associated with oncogenic mutations that led to the approval of tyrosine kinase inhibitors (TKIs) [1-2]. Considering the increased use of TKIs in clinical practice, it may be useful to identify unexpected adverse drug reactions (ADRs). Objective: The aim of this study was to describe better ADRs and to identify unexpected potential safety signals through the analysis of individual case safety reports (ICSRs) among TKIs approved for GIST collected into the European Spontaneous Reporting System (SRS) database. Methods: All ICSRs recorded starting from the drug approval up to 31 December 2021 with one of the following TKIs reported as suspected drug were included: imatinib (IM), sunitinib (SU), avapritinib (AVA), regorafenib (REG), and ripretinib (RIP). A descriptive analysis was conducted to assess all demographic characteristics. Moreover, a disproportionality analysis was performed using the Reporting Odds Ratio (ROR) with the corresponding 95% Confidence Interval (CI) to evaluate the frequency of ADRs for each TKI compared to all other TKIs. Results The number of analyzed ICSRs was 8,512 (Figure 1 Flowchart of ICSRs selection process): the 57.9% were related to IM, followed by SU (24.2%), AVA (13.1%), REG (2.7%), and RIP (2.1%). ICSRs were mainly serious (87.5%), related to males (51.7%), and to adults (44.7%);moreover, the 25.5% were fatal. The disproportionality analysis showed a higher reporting frequency of some unexpected ADRs for each TKI: gait disturbance (ROR 2.86;95% CI 1.90-4.29), hyperhidrosis (2.57;1.06-6.20), and hyperammonemia (3.92;1.05-14.60) for SU;cerebrovascular accident (6.23;2.18-17.84), hemoglobin decreased (2.23;1.08-4.61), and internal haemorrhage (14.44;3.94-52.92) for RIP;gastrointestinal ulcer (10.88;2.98-39.81) for REG;hepatic and lung cancer for IM (12.79;8.04-20.37 and 7.71;3.33-17.84, respectively);hallucination (24.33;9.02-65.68), mood swings (8.02;2.44-26.33), and stress (6.68;1.93-23.11), nephrolithiasis (6.69;2.15-20.77), pollakiuria (3.08;1.17-8.13), and dialysis (6.68;1.67-26.73), sinusitis (3.34;1.14-9.78), cellulitis (4.17;1.36-12.78), and COVID-19 (7.25;3.40-15.45), chills (2.36;1.22-4.58), limb fracture (3.53;1.63-7.60), hernia (9.23;3.71-23.00), diabetes mellitus (5.02;2.11-11.95), hyposideraemia (5.02;2.11-11.95), tinnitus (3.64;1.34-9.87), parosmia (5.00;1.12-22.38), Raynaud's phenomenon (5.00;1.12-22.38), and thyroid function test abnormal (8.90;1.99-39.83) for AVA. Conclusion: This study is largely consistent with results from literature but some unexpected ADRs were shown. Further studies are necessary to increase the awareness about the safety profiles of new TKIs approved for GISTs.

Neonatal Acute Liver Failure in a Preterm Neonate with Gestational Alloimmune Liver Disease and Congenital Portosystemic Shunts

Introduction: Gestational alloimmune liver disease (GALD) is a leading cause of neonatal acute liver failure (NALF), a rare but important diagnosis. Congenital portosystemic shunts (CPSs) are rare vascular anomalies that leave patients at risk for developing a wide spectrum of complications and have not been previously associated with GALD. In this case, we present a newborn male with NALF secondary to GALD complicated by intrahepatic shunts. Case Description: The patient is a 30 weeks gestational age male born to a 28-year-old gravida 2 para 0 mother via urgent cesarean section for severe placental malperfusion. The pregnancy was complicated by severe intrauterine growth restriction, oligohydramnios, and maternal COVID-19 infection. The patient's initial NICU course was remarkable for respiratory distress requiring ventilatory support, hypotension requiring inotropes and stress dose steroids, and coagulopathy with bleeding requiring transfusion of multiple blood products. An abdominal ultrasound showed large congenital intrahepatic portosystemic shunts. Over the course of the hospitalization, the infant progressed to fulminant hepatic failure with associated coagulopathy, hypoalbuminemia, direct hyperbilirubinemia, and hyperammonemia. There was persistent anasarca in addition to elevated ferritin (1,922 ng/dL) and alpha-fetoprotein (97,855 ng/mL). Serial SARS-CoV-2 NAAT were negative. In consultation with the hepatologist there was high clinical suspicion for GALD, and treatment with intravenous immunoglobulin was initiated, however, no clinical or laboratory improvement was noted. Abdominal MRI showed progression of the large CPSs and enlargement of the hepatic arteries. The infant continued to deteriorate, was transitioned to comfort care, and died on day of life 82. A limited autopsy revealed a markedly edematous and jaundiced male with grossly enlarged liver with hepatocellular cholestasis, portal fibrosis, diffuse hepatobiliary iron depositions, and C5b9 positivity within hepatocytes confirming a diagnosis of GALD. Discussion: Neonatal hemochromatosis is the phenotypic result of severe liver injury leading to iron overload and extrahepatic siderosis, the mechanism of hepatic injury now recognized in GALD. Liver failure in newborns with GALD often presents with marked coagulopathy, hypoalbuminemia, and edema with and without ascites. The establishment of the diagnosis is crucial given without treatment, the prognosis is very poor. There have been no case reports of neonates with acute liver failure from CPSs or CPSs occurring with GALD. We hypothesize that the presence of CPSs worsens the clinical course of GALD through an unknown mechanism that further expedites hepatocellular damage. Furthermore, the role of SARS-CoV-2 infection and transmission in the neonatal population is still unknown. Conclusion: Neonatal acute liver failure caused by GALD is a rare but potentially fatal diagnosis. CPSs associated with GALD have not been previously documented. This case demonstrates the interplay of these disease entities likely contributing towards a more severe course of NALF and highlights the importance of early identification for guiding management. (Figure Presented).

Prolonged ECMO Support of an Adult with SARS-CoV-2 ARDS and Right Heart Failure in a Children's Hospital

ECMO has become a widely recognized support modality for patients with severe cardiac or respiratory failure, and has been increasingly utilized in the ongoing severe acute respiratory syndrome due to coronavirus-2 (SARS-CoV-2) pandemic. Long-term support on ECMO for acute respiratory distress syndrome (ARDS) is also becoming more commonplace with eventual lung recovery, obviating the need for lung transplantation. However, long-term ECMO support has not been well studied for SARS-CoV-2 ARDS patients. We report the case of a 39-year-old female with severe SARS-CoV-2-induced ARDS successfully supported on venovenous ECMO (V-V ECMO) for 5,208 hours (217 days) in a high ECMO-volume, quaternary care children's hospital in 2021. At the time of this writing, this is the longest reported patient successfully supported on ECMO for SARS-CoV-2 ARDS. Our patient was initially cannulated at our children's hospital with dual-site V-V ECMO, via the right internal jugular vein (RIJ) and right common femoral vein. Bedside tracheostomy was performed on ECMO day 40, for early mobility, oral feeding, interaction, and pulmonary rehabilitation planning. Unfortunately, during her course she suffered multiple complications including bacterial co-infections, bleeding requiring anticoagulant changes from unfractionated heparin (UFH) to bivalirudin, multiple ECMO circuit changes due to blood product consumption and coagulopathy, and pneumothoraces requiring thoracostomy tube placements. Approximately 1.5 months into her ECMO course, she suffered acute hypoxemia and echocardiography revealed indirect evidence of pulmonary hypertension with right heart failure. Initial right heart catheterization while on V-V ECMO revealed elevated right ventricular end-diastolic pressure (RVEDP=15-20 mmHg) and severe systemic desaturation with main pulmonary artery (MPA) pressure of 30 mmHg. Pulmonary hypertension and right heart support was initiated in the form of inhaled nitric oxide (iNO), inotropes, phosphodiesterase inhibitors, nitrates, angiotensin-converting enzyme inhibitors, and diuresis. Ultimately, due to necessity of right-heart decompression and support, on ECMO day 86 she was transitioned to single-site V-V ECMO utilizing a 31 Fr dual-lumen venovenous cannula (ProtekDuo (LivaNova, UK)) placed via her RIJ through her right atrium (RA) into the MPA in the cardiac catheterization laboratory. Subsequent heart catheterization more than 2 months later revealed severe right ventricular (RV) diastolic dysfunction (RVEDP=35 mmHg) and moderate left ventricular (LV) diastolic dysfunction (pulmonary capillary wedge pressure (PCWP=24 mmHg)). During her course, multiple trials off ECMO were attempted with varying lengths of time off ECMO support, but ultimately required ongoing ECMO support. She developed evidence of end-organ dysfunction from her cor pulmonale, including oliguric renal failure requiring renal replacement therapy (RRT), hepatic injury with elevated transaminases and hyperammonemia leading to depressed mental state, feeding intolerance, and coagulopathy. Additionally, due to long-term nasogastric enteral tube placement for caloric supplementation and enteral medication administration, she developed concerns for invasive sinusitis with erosion into ethmoid and maxillary sinuses. As she was an adult patient being cared for in a free-standing academic children's hospital, multiple adult medicine consultants were involved in her care. Specifically, adult nephrology, cardiology, cardiothoracic surgery (for ProtekDuo cannula placement), and gastroenterology/ hepatology were integral into her care, along with our pediatric critical care medicine and ECMO teams. Notably, this was the first patient supported on ECMO to receive tracheostomy, RA-MPA dual-lumen VV cannula, and full autonomous mobility outside of the ICU at our well-established ECMO program, which has served as the index patient leading to future advances in the care of our ECMO patients. Over time and with multiple therapies to alleviate her cor pulmonale, the patient's echocardiograms evealed improved, half-systemic right-sided cardiac pressures. She was ultimately decannulated from ECMO at our center before being transferred back to the referring adult facility, and discharged to home 8 months after her initial presentation with acute respiratory failure.

Hyperammonemia is a risk factor for poor outcomes in patients with COVID-19

Objective. We analyzed clinical features and laboratory markers of COVID-19 patients according to favorable outcomes versus fatal outcomes. Material and methods. The medical history of 80 patients was analyzed: 51 patients with favorable outcomes were included in group №1, 29 patients with a fatal outcome were included in group №2. Demographic data, duration of the disease, comorbid-ities, laboratory markers, and results of the instrumental studies were included. The ammonia level in the peripheral blood was de-termined by the express method using a PocketChem BA 4140 photometric portable analyzer. Results. Patients in group №2 were older (68±11 years) had hypertension stage 3 with high cardiovascular risk;every third had a history of myocardial infarction. At admission, patients from group №2 were most likely with febrile fever and high levels of inflammatory markers — predictors of a cytokine release syndrome. In addition, 71% of patients at admission had elevated ammonia levels. Hyperammonemia correlated with high ferritin levels, leukopenia, non-alcoholic fatty liver disease in patients, and lethal outcomes. Conclusions. The risks of poor COVID-19 outcomes are higher in comorbid patients of the older age group. Hyperammonemia may be one of the predictors of poor COVID-19 outcomes. © 2022, Media Sphera Publishing Group. All rights reserved.

Epidemiology, Clinical Presentation and Treatment of Non-Hepatic Hyperammonemia in ICU COVID-19 Patients.

(1) Background: Although COVID-19 is largely a respiratory disease, it is actually a systemic disease that has a wide range of effects that are not yet fully known. The aim of this study was to determine the incidence, predictors and outcome of non-hepatic hyperammonemia (NHH) in COVID-19 in intensive care unit (ICU); (2) Methods: This is a 3-month prospective observational study in a third-level COVID-19 hospital. The authors collected demographic, clinical, severity score and outcome data. Logistic regression analyses were performed to identify predictors of NHH; (3) Results: 156 COVID-19 patients were admitted to the ICU. The incidence of NHH was 12.2% (19 patients). The univariate analysis showed that invasive mechanical ventilation had a 6.6-fold higher risk (OR 6.66, 95% CI 0.86-51.6, p = 0.039) for NHH, while in the multiple regression analysis, there was a 7-fold higher risk for NHH-but it was not statistically significant (OR 7.1, 95% CI 0.90-56.4, p = 0.062). Demographics, clinical characteristics and mortality in the ICU at 28 days did not show a significant association with NHH. (4) Conclusions: The incidence of NHH in ICU COVID-19 patients was not low. NHH did not appear to significantly increase mortality, and all patients with non-hepatic hyperammonemia were successfully treated without further complications. However, the pathogenesis of NHH in ICU patients with COVID-19 remains a topic to be explored with further research.

Compound heterozygote variants: c.848A > G; p.Glu283Gly and c.890C > T; p.Ala297Val, of Isovaleric acid-CoA dehydrogenase (IVD) gene causing severe Isovaleric acidemia with hyperammonemia.

With the execution of expanded newborn screen (NBS) program nationwide, it is uncommon to see severe hyperammonemia associated with isovaleric acidemia (IVA). We present a seven-day-old boy with severe IVA complicated by hyperammonemia. This child was flagged by NBS at 4 days old, but confirmatory testing was delayed due to COVID19 pandemic and parental skepticism. His parents did not adhere to the leucine-restricted diet as recommended. On day 7, the patient presented to the ER with ammonia of 588 µg/dL. Ammonia subsequently rose to >1000 µg/dL. This child received carnitine, 1 dose of Ammonul (sodium benzoate and sodium phenylacetate), arginine, carglumic acid (Carbaglu) and CRRT. Plasma amino acid assay revealed a glutamine level of 256 µmol/L, which is below the lower limit of normal upon arrival to ER and PICU. The hyperammonemia was corrected in 15 h and with the continued use of carglumic acid for 3 days, there was no rebound of hyperammonemia. However, the patient suffered from bone marrow suppression associated with the organic acidemia and required frequent platelet transfusions, as well as G-CSF for neutropenia. The management of this patient provides supporting evidence of the many theoretic metabolic "facts" including why Ammonul is not helpful in organic acidemias.

P.0177 Partial ornithine-transcarbamylase deficiency, autoimmunity and psychosis – a complex case report

Background: Ornithine-transcarbamylase deficiency (OTC) is the most common type of urea cycle disorder, and it is the only one with X-linked inheritance. The clinical presentations can vary from severe symptoms caused by hyperammonemia in childhood or adolescence to milder cases with late-onset in adulthood (similar to delirium or acute psychosis) [1], in the context of precipitating factors such as pregnancy, high protein intake, acute stress, infections, certain medications (valproate, steroids, haloperidol) [2]. Method: We present a case of a 31-year-old female, with no history of mental disorders, with a personal history of Hashimoto thyroiditis and urticaria, and a family history of OTC deficiency (her two-year-old niece). She was also a heterozygous carrier for the OTC deletion, reporting periods of meat avoidance and anorexia. She was single, lived alone, and complained of work-related stress, mainly as she worked from home during the COVID-19 pandemic as an IT consultant. The patient presented at our clinic in emergency for psychomotor agitation, slurred speech, complex auditory and visual hallucinations, and mystical delusional ideas. Furthermore, one week before her presentation, she started fasting because of her Christian orthodox religious beliefs (before Easter celebration), but she also complained of insomnia, fatigue, and tachycardia. The patient reported being vaccinated with the first dose of Pfizer's SARS-CoV-2 vaccine one week before the presentation. Results: Laboratory tests showed iron-deficient anemia and ketonuria;hepatic function was normal. Thyroid function was also normal, but anti thyroperoxidase antibodies were elevated. Serum ammonia levels were normal, and urinary orotic acid levels were within normal range. The result of head CT was unremarkable. Neurological examination was normal. She was started on 10 mg i.m. Haloperidol per day, but given the possibility of inducing hyperammonemia in urea cycle disorders patients, she was switched to Risperidone 6 mg/day, which was gradually reduced to 3 mg/day. Also, she was started on a protein-restricted diet. On the second and third days of admission, she was partially disoriented and somnolent but showed no signs of metabolic encephalopathy;therefore, metabolic treatment was not initiated. On the sixth day, she was almost completely recovered, with no psychotic symptoms. After the remission of psychotic symptoms, the neuropsychological evaluation showed significant cognitive deficits: executive functions (impaired performance on Tower of London task), deficits of focused and distributed attention, and decreased immediate verbal memory, even though the patient had received higher education, being at the top of her class during her studies. Given that metabolic profiles were normal, we discuss the complex interactions between autoimmune disorders, genetic factors, precipitating factors, and psychosocial factors that could have contributed to the psychotic episode. Conclusion: Clinicians should consider various factors that can influence the psychological state of a patient, paying attention to atypical factors or symptoms. Also, regarding the treatment of psychiatric symptoms in patients with urea cycle disorders with a normal metabolic profile, psychiatrists must avoid certain medications (haloperidol, valproate) that can worsen the patient's status. No conflict of interest

Clostridium Difficile and Noncirrhotic Hyperammonnemia in a Patient With COVID-19 Infection.

Clostridium difficile is a bacterial infection that usually presents with diarrhea and is mostly associated with previous antibiotics use. Patients with coronavirus disease 2019 (COVID-19) generally have respiratory symptoms but can also present with diarrhea. Noncirrhotic hyperammonemia is an infrequent presentation and is treated with lactulose. We report the case of a 40-year-old male who was admitted to our hospital with abdominal pain, diarrhea, shortness of breath, and confusion. During hospitalization, the patient tested positive for COVID-19 and C. difficile, and oral vancomycin was administered. His kidney functions improved, but he remained confused. His ammonia levels were elevated, and he was not treated with lactulose due to ongoing diarrhea secondary to C. difficile infection.