The First Reported Case of Lorlatinib-Associated Diabetic Ketoacidosis

Introduction: Lorlatinib is a third-generation tyrosine kinase inhibitor that inhibits anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1). Although 2-10% of patients with non-small cell lung cancer developed hyperglycemia in phase 2 and 3 studies of lorlatinib, only one case has subsequently reported hyperglycemia >500 mg/dL, and no cases of diabetic ketoacidosis (DKA) have been previously reported. Phase 1 trials in neuroblastoma are ongoing. Case Description: A 34-year-old woman with ALK-mutated paraspinal neuroblastoma presented with DKA 14 months after initiation of lorlatinib. Prior to starting lorlatinib, her hemoglobin A1c had been 5.0% (n: < 5.7%). After 12 months of therapy, her A1c increased to 7.8%, prompting the initiation of metformin 500 mg daily. However, two months later she was admitted for DKA with a blood glucose of 591 mg/dL (n: 65-99 mg/dL), CO2 17 mmol/L (n: 20-30 mmol/L), anion gap 18 (n: 8-12), moderate serum ketones, and 3+ ketonuria. Her A1c was 14.8%, C-peptide was 1.2 ng/mL (n: 1.1-4.3 ng/mL), and her glutamic acid decarboxylase-65 and islet antigen-2 autoantibodies were negative. She was also found to be incidentally positive for COVID-19 but was asymptomatic without any oxygen requirement. The patient's DKA was successfully treated with IV insulin infusion, and she was discharged after 3 days with insulin glargine 27 units twice daily and insulin aspart 16 units with meals. One month later, her hemoglobin A1c had improved to 9.4%, and the patient's oncologist discontinued lorlatinib due to sustained remission of her neuroblastoma and her complication of DKA. After stopping lorlatinib, her blood glucose rapidly improved, and she self-discontinued all her insulin in the following 3 weeks. One month later, she was seen in endocrine clinic only taking metformin 500 mg twice daily with fasting and post-prandial blood glucose ranging 86-107 mg/dL. Discussion(s): This is the first reported case of DKA associated with lorlatinib. This case highlights the importance of close glucose monitoring and the risk of severe hyperglycemia and DKA while on lorlatinib therapy. Discontinuation of lorlatinib results in rapid improvement of glycemic control, and glucose-lowering treatments should be promptly deescalated to avoid hypoglycemia.Copyright © 2023

Clinical Dilemma of Diabetic Ketoacidosis and COVID-19 Infection

The COVID-19 Pneumonia with diabetic ketoacidosis is a dreadful health condition. Diabetic ketoacidosis is one of the severe metabolic complications and it can be precipitated by infection. We presented a case of 48 years female with no known comorbidities who presented with COVID-19 symptoms and with Diabetic Ketoacidosis. The case presented with elevated inflammatory markers, high anion gap metabolic acidosis with type I respiratory failure. During admission, the oxygen saturation had marked drop, later her improvement was steady followed by gradual tapering of the oxygenation. Marked improvement was noticed in the subsequent follow-up. COVID-19 infection can be precipitated by preexisting diabetes or newly diagnosed diabetes and the severity of COVID-19 infection is more pronounced in patients with diabetes mellitus, thus should be managed timely and accordingly. The scarce studies among the COVID-19 cases with diabetic ketoacidosis reflect the need for further studies for the availability of a wider range of information. Copyright © 2021, Kathmandu University. All rights reserved.

ELEVATED ANION GAP AS A MARKER OF SEVERE SARS-COV-2 INFECTION IN PREGNANT PATIENTS WITHOUT DIABETES: A CASE SERIES

SESSION TITLE: Biological Markers in Patients with COVID-19 Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: 10/18/2022 01:30 pm - 02:30 pm PURPOSE: In December 2019, a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) resulted in a global pandemic. The literature has been slowly growing in the subgroup of pregnant women but the metabolic derangements of pregnancy and SARS-CoV-2 have not been well described. METHODS: In this case series, we review 9 patients with severe SARS-CoV-2 infections admitted to the medical ICU at a single institution between 2020-2022, during the delta variant wave. RESULTS: Of the nine critically ill patients, the mean age was 32 ± 6.4 years with fetal age on admission of 27 ±2.81 weeks and 29 ±2.91 weeks at delivery. Average CRP of 114 ± 25 mg/L. In eight of 9 patients (89%), there was an anion gap metabolic acidosis (AGMA) on admission. The average albumin-corrected anion gap was 18±1.93. 75% of patients had mild ketonuria based on urinalysis. However, 50% had documented symptoms of nausea, vomiting, or diarrhea. While betahydroxybutyrate was checked in 2 patients, neither were abnormal. One had lactic acidosis, but none required vasopressors at time of identification. No renal failure or diabetes was noted and only two had abnormal glucose tolerance tests. At delivery, average PEEP was 10± 4 cmH2O with an average respiratory rate of 28 ± 4 breaths per minute. All patients with AGMA delivered early resulting in preterm delivery. 75% of the fetuses showed signs of distress at the time of delivery, which was the primary indication for delivery in 37.5% of deliveries. 37.5% of deliveries were due to significant maternal hypoxia. The only patient without AGMA did not deliver early. CONCLUSIONS: After excluding renal failure, toxin ingestion, and lactic acidosis, only ketosis can weakly explain the AGMA. There have been several studies that highlighted the association between COVID and ketone production. In pregnancy, placental production of glucagon and human placental lactogen and subsequent insulin resistance increases susceptibility to ketosis. A recent study posited that COVID could cause placental abnormalities. Therefore, pregnant women may be more susceptible to significant ketosis because of COVID infection. In one of our cases, the combination of hypoxia and acidosis could not be managed safely by the ventilator and resulted in early delivery. CLINICAL IMPLICATIONS: Ketosis and an elevated anion gap could be a marker for more severe outcomes in pregnant patients with COVID. This case series highlights the challenges of managing the metabolic demands of critically ill pregnant patients infected with SARS-CoV-2. DISCLOSURES: No relevant relationships by Calli Bertschy no disclosure on file for Joey Carlin;No relevant relationships by Jessica Ehrig No relevant relationships by Shekhar Ghamande no disclosure on file for Jordan Gray;No relevant relationships by Abirami Subramanian

An Unusual Case of Autoantibody-Negative KetosisProne Diabetes (KPD) Secondary to Marked Insulin Resistance

KPD is classically regarded as an atypical form of diabetes caused by near-complete beta-cell failure. A 37-year-old Egyptian man (BMI: 27.7 Kg/m2) presented with hyperglycemia (362 mg/dL) and DKA (arterial pH 7.20, ketonemia 5.0 mmol/L, ketonuria 80 mg/dL) . He was afebrile, with recent polyuria, polydipsia and weight loss. HbA1c was 107 mmol/mol (11.9%) and blood tests excluded diabetes secondary to endocrinopathies. SARS-CoV-2 RT-PCR test was negative. IV insulin infusion (0.1 IU/kg/h) and IV fluid therapy were started. He was shortly transitioned to a sc basal-bolus insulin regimen (0.7 IU/kg/day) . Mixed-meal tolerance test (MMTT) revealed a peak 120-min stimulated C-peptide of 12.3 ng/mL, suggesting marked insulin resistance. Islet autoantibodies (ICA, IAA, GADA, IA-2A, ZnT8A) and insulin receptor autoantibodies (IgG/IgM) were negative. HLA genotyping detected the following haplotypes: DRB1∗01, ∗04;DQA1∗01:01P, ∗03:01P;DQB1∗03:02P, ∗05:01P. Insulin dose was gradually reduced and insulin therapy was discontinued after 4 months in favor of metformin (2550 mg/day) plus sc semaglutide (up to 1 mg/week) . After one year, MMTT revealed a peak 60-min stimulated C-peptide of 8.25 ng/mL. During the 18-month follow-up period, fasting capillary beta-hydroxybutyrate values were <0.2 mmol/L and HbA1c remained <48 mmol/mol (<6.5%) , indicating disease remission. This case suggests the existence of an autoantibody-negative KPD subtype driven by marked insulin resistance rather than by insulinopenia.

COVID-19 associated mixed mold infection: a rare case report of aspergillosis and mucormycosis

Background: Fungal epidemic was announced amid COVID pandemic with several cases of COVID-associated Mucormycosis and Aspergillosis being reported however there is not sufficient data regarding mixed fungal infection. Case Study: A 54-year-old male patient diagnosed with severe COVID 19 pneumonia and diabetes 1-month back presented to OPD with C/O of chest pain and breathlessness for two days associated with haemoptysis, heaviness and congestion of right nostril but no fever. O/E patient was tachypnoeic, hypoxic and in shock, Neutrophil count 87%, RBS-530 mg/dl, urine ketone body was absent. Chest x-ray showed opacity over the left upper and mid-zone, HRCTthorax showed a bird-nest-sign noted in the left upper lobe S/O invasive fungal infection. MRI PNS showed mucosal thickening S/O sinusitis, Fungal infection. Sino-nasal mucosa KHO-mount and fungal culture showed mixed infection of Rhizopus species and aspergillus flavus. Right nasal HP study showed mixed invasive moulds infection. Initially, the patient was treated conservatively later on inj. amphotericin-B was started. The patient's condition worsened on day-18 and succumbed a day later. Discussion: Uncontrolled diabetes-mellitus, and corticosteroids leading to hyperglycaemia, extensive use of broad-spectrum antibiotics increases the risk of invasive Moulds. In our case study, patients suffered from COVIDpneumonitis and had uncontrolled diabetes leading to damage of airway epithelium inviting an invasion of tissues by moulds. Conclusion: Mixed fungal infections as COVID-19 sequelae may be an emerging issue and seen particularly in post- COVID patients with uncontrolled diabetes, and on steroids. The focus should be on prompt management: hit hard approach with both medical and surgical treatment.

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

New onset diabetes in a boy with multi-system inflammatory syndrome in children (MIS-C) following SARS-CoV-2 infection

Introduction: Case report Objectives: During the past year, COVID-19 infection was recognized as a potential trigger for new onset diabetes in children. A rare but severe complication of COVID-19 infection in children and adolescents is multisystem inflammatory sindrome in children (MIS-C). We describe a case of newly diagnosed diabetes mellitus (DM) in a tenyear old patient during the course of MIS-C. Methods: Case report Results: A ten-year-old previously healthy male presented with vomiting and painful and enlarged lymph nodes. He was febrile to 39.4°C and tachycardic to 124 beats/minute. Initial laboratory evaluation was notable for acute infection, but the child also had hyperglycemia, ketonuria, glycosuria. Empiric antibiotic therapy was started, but he was persistently febrile, had lymphadenopathy with redness of the surrounding skin and developed conjunctival injection and a discrete livid erythema on the trunk. His follow up labs showed leukopenia with lymphocytopenia and neutrophilia, anemia and thrombocytopenia and upsurge of inflammation markers. Other possible causes of his condition were excluded and he tested positive for anti-SARS-CoV-2 IgM and IgG via immunochromatographic assay. Criteria for MIS-C was met, and intravenous immunoglobulin treatment was started which yielded immediate recovery. During the acute course of MIS-C his blood glucose levels were up to 15.5 mmoL/L, with no disturbances in acid-base status. Since high glucose levels and glucosuria persisted beyond resolution of the MIS-C, and HbA1c was elevated (7.8%), the patient was started on intensified therapy with insulin analogues. Islet-cells autoantibodies were only marginally elevated (GAD-65 1.9 and IA-2A 1.8 kIU/L) and C-peptide was normal. Conclusions: In pediatric population inflammatory syndromes like MIS-C can raise the risk for diabetes development or presentation. Therefore it is important to monitor glycemia during the course of MIS-C and also during post-inflammatory follow-up.