Biochemical Improvement Research Articles

P1072 Upadacitinib appears effective in inducing clinical, biochemical, endoscopic and histologic improvements in previously treatment refractory Ulcerative Colitis

Abstract Background Upadacitinib is a novel, oral agent which acts by inhibition of JAK signaling. It has proven efficacy in large-scale, randomised trials for the treatment of UC. We report our real-world experience of upadacitinib as induction therapy in a single centre study of UC patients, including patients who were refractory or intolerant of other advanced therapies. Methods We performed a retrospective analysis of outcomes in patients who were commenced on upadacitinib for UC at a tertiary IBD centre between October 2022 to October 2023. The parameters used to assess disease activity were the Simple Clinical Colitis Activity Index (SCCAI), faecal calprotectin (FCP), Ulcerative Colitis Endoscopic Index of Severity (UCEIS) and Nancy Histological Index (NHI). Clinical response was defined as a reduction of SCCAI of ≥3 points, clinical remission as SCCAI of ≤2, biochemical remission as FC<150ug/g. Endoscopic remission was defined as UCEIS 0-1 and histological remission as NHI 0-1. Medical records were reviewed for patient-reported adverse events. Wilcoxon matched-pairs signed rank test was used to compare pre- and post-treatment continuous variables. Results 42 patients were started on 45mg once daily upadacitinib over this period. 20 were female, the mean age was 39. 31 had left sided disease, 8 had pancolitis. 39 (93%) patients had prior experience of advanced therapy and 22 (52%) had ≥2 prior therapies. At baseline, mean SCCAI was 7 (1-15), and mean FCP 1328 (42-6810) μg/g. Baseline endoscopy demonstrated a mean UCEIS of 5 (3-7) and baseline histology a mean NHI of 3 (1-4). At the 6-week follow up, paired data on clinical and biochemical responses were available in 23 and 27 patients respectively, showing an improvement to a mean SCCAI of 3 (p=0.0004) and mean FCP of 491 μg/g (p=0.002). 16 (70%) achieved clinical response, 14 (61%) were in clinical remission. 15 (56%) had a reduction in FCP to <150 μg/g. Endoscopic reevaluation took place after a minimum of 12 weeks on treatment. Paired endoscopic outcomes in 20 patients demonstrated an improvement of UCEIS to a mean of 1 (p<0.0001), with 16 (80%) patients in endoscopic remission. Week 12 histology showed improvement to a mean NHI of 2 (p<0.0001, n=19), with 9 (47%) patients achieving histological remission. 6 (14%) patients were non-responders. 3 required a colectomy, 2 necessitated a switch in medical therapy, 1 remained on extended induction. 3 patients (7%) reported facial acne as an adverse event, no others were reported. Conclusion Upadacitinib appears effective at inducing significant clinical, biochemical, endoscopic and histological improvements within 12 weeks, amongst a real-world cohort of patients with moderate-to-severe UC that has proved refractory to other advanced therapies.

Intensification with Intravenous Ustekinumab in Refractory Crohn’s Disease

Background: The rates of clinical and biochemical responses in Crohn’s disease (CD) patients treated with intravenous (IV) ustekinumab (UST) intensification are scarcely described. Methods: Patients with diagnosis of CD who were under intensified IV ustekinumab treatment (130 mg every 4 weeks) were retrospectively included, evaluating the clinical and biochemical response 12 weeks after the change in treatment regimen (switch from SC to IV), as well as the serum levels of the drug. Results: Twenty-seven patients, all of whom had transitioned to intensified intravenous ustekinumab treatment due to a secondary loss of response to the drug, were included in the retrospective analysis. At the baseline visit, prior to changing IV UST, differences in levels were observed between intensified and non-intensified patients (7216 vs. 2842 ng/mL, p = 0.00005). However, no significant differences were found between these two groups 12 weeks after IV intensification (7949 vs. 7937 ng/mL; p = 0.99). In patients with previous intensified UST SC, a decrease in fecal calprotectin was observed 12 weeks after starting IV intensification, going from a mean of 1463 ug/g to 751 ug/g, although the differences were not significant (p = 0.14). Conclusion: In our experience, intensifying treatment with IV UST leads to clinical and biochemical improvements in CD patients with a secondary loss of response to SC maintenance with this drug, and an increase in drug levels was observed 12 weeks after IV UST intensification.

P723 Upadacitinib in Crohn’s disease: Real world experience from an early access program in Greece

Abstract Background Upadacitinib is a novel selective Janus kinase 1 inhibitor, recently approved for the management of Crohn’s disease (CD) by Food and Drug Administration. In Greece, upadacitinib is available through an early access program for refractory patients who have exhausted their therapeutic options. Our goal was to describe our real practice experience. Methods This is a multicenter retrospective cohort study of adult patients with moderate to severe CD, who received upadacitinib. The primary endpoint was clinical response, defined by a reduction ≥3 in Harvey-Bradshaw index (HBI). Clinical remission was defined as HBI ≤4. Secondary endpoints included endoscopic and biochemical improvement based on physician’s assessment and CRP measurement, respectively. Outcomes were assessed at 12 weeks and at patient’s latest follow up. All patients received 45mg upadacitinib for 3 months and then 30mg for another 3 months, whereas the maintenance dose (30mg or 15mg) was based on the patient’s response. We also evaluated short -term safety. Results A total of 22 CD patients (12 female) received upadacitinib and were included in the analysis. Mean age 42.2 years (24-63). Five patients were active smokers. Mean treatment duration was 5.4 months (1-20). Two patients have not yet reached 12 weeks of treatment and were excluded from the efficacy analysis. Ten patients (45.4%) had ileocolonic Crohn’s, seven (31.8%) ileal disease and five (22.7%) Crohn’s colitis. Four patients had perianal disease and seven patients Crohn’s related surgery (5 ileocecal resection, 2 seton placement). Four patients had active extraintestinal manifestations: Three inflammatory arthritis and one atopic dermatitis. The majority of patients (15/20) had failed ≥ 3 biologics. All of them failed treatment with anti-TNF and 15 (75%) with ustekinumab. Six patients have just completed the induction period of 12 weeks, ten are on 30mg upadacitinib and four on 15mg. At 12 weeks, 18 patients achieved clinical response (90%). CRP was normal for 15/20 (75%) patients at 12 weeks. At last follow-up (mean 5.9 months, 3-20), all patients were in clinical remission. Endoscopy was available for six patients and improvement was documented for all of them. Adverse events occurred in 3 patients (15.7%): An episode of abdominal pain, a skin infection and a case of neutropenia. All adverse events resolved without discontinuing treatment. Conclusion In a small cohort of medically resistant Crohn’s patients, the short- term clinical efficacy of upadacitinib was high. No serious safety issues were recorded.

Durvalumab-Induced Triple-M Syndrome.

While the use of immunotherapy has revolutionised the treatment of various cancers, it is often associated with a myriad of immune-related adverse effects. In this article, we report a rare case of durvalumab-induced triple-M syndrome in a 69-year-old woman with stage III lung adenocarcinoma. She was admitted with profound generalised muscle weakness, myalgia, and exertional breathlessness, about a week into her second cycle of durvalumab, an immune checkpoint inhibitor. She had clinicopathological features of myositis, myasthenia and myocarditis with acute onset symptomatic tri-fascicular block on electrocardiogram, requiring urgent cardiology intervention. Durvalumab was discontinued and she was treated with a combination of high-dose steroids and intravenous immunoglobulin after which she had clinical and biochemical improvement, albeit with residual muscle weakness. Myocarditis-myositis-myasthenia complex is a rare side effect of immunotherapy which has been reported in other immune checkpoint inhibitors, but less so with durvalumab. We report this clinical case to raise awareness of this rare and potentially life-threatening adverse effect of this agent. Triple-M syndrome is a rare immune-related adverse effect, which has been noted in other immune checkpoint inhibitors, but less so with durvalumab specifically.Immunotherapy-induced myositis, myocarditis and myasthenia can occur in isolation or, rarely, in association as a syndrome.This case demonstrates the potentially life-threatening nature of this entity, the need for early recognition, and multi-specialist teamwork to ensure good outcome.

Bee Sting-induced Nephrotic Syndrome in a Child: A Case Report with Review of Literature

Abstract Background: Nephrotic syndrome (NS) is common in children, and it is usually idiopathic. Bee sting-induced NS in children is rarely reported. Clinical Description: A 9-year-old female child presented with a complaint of generalized edema for 2 days which started to develop 4 days after being stung on the dorsum of her right foot by a bee. She had pedal edema, facial puffiness, and abdominal distension. Management and Outcome: Laboratory investigations showed proteinuria, low serum protein, elevated serum cholesterol, serum triglycerides, and immunoglobulin E levels. A diagnosis of NS secondary to bee sting was made. The patient was treated with supportive measures for edema. There was a significant clinical and biochemical improvement by 10 days. Conclusion: This case reiterates the association between allergen exposure and NS, which is hardly reported in children. Such a phenomenon may be transient with requirement of only supportive therapy for symptom relief.

Função do Ventrículo Direito e Estresse Oxidativo Melhoram com a Administração de Hormônios da Tireoide e Suco de Uva em um Modelo de Hipertensão Pulmonar

Abstract Background Adverse remodeling of lung vessels elevates pulmonary pressure and provokes pulmonary arterial hypertension (PAH). PAH results in increased right ventricle (RV) afterload, causing ventricular hypertrophy and the onset of heart failure. There is no specific treatment for maladaptive RV remodeling secondary to PAH. Objectives This study aims to explore two therapeutic approaches, grape juice (GJ) and thyroid hormones (TH), on PAH-induced oxidative stress and cardiac functional changes. Methods Parameters of echocardiography related to lung vessel resistance (AT/ET ratio), RV contractility (TAPSE), and RV diastolic function (E/A peaks ratio) were evaluated. Also, total ROS, lipid peroxidation, antioxidant enzymes, calcium handling proteins, pro-oxidant and antioxidant protein expression were measured. Values of p<0.05 were considered statistically significant. Results Both GJ and TH treatments demonstrated reductions in pulmonary resistance (~22%) and improvements in TAPSE (inotropism ~11%) and AT/ET ratio (~26%) (p<0.05). There were no changes amongst groups regarding the E/A peak ratio. Although ROS and TBARS were not statistically significant, GJ and TH treatments decreased xanthine oxidase (~49%) levels and normalized HSP70 and calcium handling protein expression (p<0.05). However, only TH treatment ameliorated diastolic function (~50%) and augmented NRF2 immunocontent (~48%) (p<0.05). Conclusions To the best of our knowledge, this study stands as a pioneer in showing that TH administered together with GJ promoted functional and biochemical improvements in a PAH model. Moreover, our data suggest that GJ and TH treatments were cardioprotective, combined or not, and exhibited their beneficial effects by modulating oxidative stress and calcium-handling proteins.

A Young Farmer with Multi-Organ Failure: A Case Report on Weil’s Disease in Bangladesh

Weil’s disease is a zoonotic infection caused by organism of Leptospira icterohaemorrhagiae, having a very high mortality. This article reports a case of a young male farmer who presented to a tertiary-level hospital in north-eastern Bangladesh with severe fatigue, fever, abdominal pain and yellow discoloration of the whole body. Meticulous history taking revealed that he worked bare-footed in an animal farm and had a cut injury in his right foot 15 days back. On the basis of this piece of information, serological tests for leptospirosis were done that showed positive results. There was significant clinical and biochemical improvement after treatment. This case report revealed that a patient with fever, hepatitis and, pancreatitis with a background history of suggestive exposure, leptospirosis should be considered.

STUDY OF THE INTERDEPENDENCE OF THE CONTENT OF PROTEIN FRACTIONS AND ALKALINE PHOSPHATASE IN THE BLOOD OF COWS WITH INDICATORS OF REPRODUCTIVE ABILITY

Increasing the production of dairy and meat products is becoming more and more important in connection with the growth of the population and the increase in demand for these products. In order to meet the needs of the consumer in this matter, directions for increasing the reproductive capacity of livestock are constantly being developed, because this issue is becoming more acute every year. The aim of the study was to establish the dependence of biochemical indicators, such as the content of total protein, albumins, the ratio of albumins to globulins and alkaline phosphatase with indicators of reproducibility. Blood serum was used to determine biochemical parameters. The method for determining the content of total protein, albumins, alkaline phosphatase activity was based on the use of the spectrophotometric method. Statistical analysis was performed using Microsoft Excel. According to the results of our research, a statistical interdependence of the protein content with indicators of the service period, reproducibility, and insemination index was established, where the correlation dependence was within r= (-0.471 – (-0.809)) with a probable error (P<0.001). A correlation dependence of alkaline phosphatase activity with indicators of reproducibility was established, which had statistical limits of r= 0.602 to -0.722 with a probable error (P<0.001). During the analysis of scientific works, a similarity was established in the dependence of changes in biochemical blood parameters and their influence on the reproductive capacity of the cow herd. These changes in the application of food additives in the diet of animals to correct metabolism, which led to changes in biochemical indicators and improvement of reproductive capacity, are quite clearly traced.

Decoding Type 2 Diabetes Through Point-of-Care Testing, Cloud-based Monitoring, and Generative Augmented Retrieval Model-driven Virtual Diabetes Education: A Comprehensive Approach to Glycemic Control

Abstract In a type 2 diabetes study, participants in the intervention group, exposed to artificial intelligence-driven diabetes nudges, exhibited remarkable ameliorations compared to the control cohort receiving standard care. Notable biochemical improvements included a significant mean reduction in hemoglobin A1C levels by 1.25, indicating enhanced glycemic control over the protracted term. Furthermore, the intervention group manifested a substantial plasma glucose delta of 26.1, denoting improvements in short-term glycemic indices. In-depth analyses unearthed favorable impacts on various glycemic parameters: A noteworthy glycemic cap enhancement of 0.97, a pronounced postprandial glucose decrement by 49.48, and a discernible glucose score reduction of 3.94. In addition, the intervention engendered favorable shifts in dietary metrics, as evidenced by the food zone improvement (6.49) and food comparison elevation (6.12). These findings, bolstered by robust statistical analyses and graphically depicted trends, underscore the intervention’s efficacy in instigating comprehensive advancements in glycemic control, both immediate and sustained, as denoted by the intricate web of medical parameters assessed in this comprehensive investigation.

BIOCHEMICAL PROFILE OF FULL-TERM NEWBORNS WITH DIFFERENT PROTEIN SUPPLY ON THE BACKGROUND OF THE TREATMENT OF CRITICAL DISEASES OF THE PERINATAL PERIOD

Study of the effect of increased protein and L-carnitine supplementation in term neonates with critical illnesses on the biochemical profile and improvement of intensive care outcomes.
 Objective: assessment of the impact of increased L-carnitine and protein supplementation on the physical development and biochemical profile of newborns who were in a critical condition.
 Materials and methods. The life indicators of 59 full-term children, who were randomly divided into two groups, were studied. The first group (n = 30) received standard nutrition with mother's milk or formula, the second group (n = 29) received protein-fortified food and L-carnitine supplementation during the hospital stay.
 The results. Babies of both groups had statistically equivalent characteristics at the beginning of the study. Against the background of higher consumption of proteins, the number of non-protein calories per 1 g of protein in the study group was 28.68 kcal/kg/day (27.50; 29.80), against the indicator of the standard diet group of 42.37 kcal/kg/day (41 .60; 38.00), with U = 28.0000; p = 0.000001. Carnitine supplementation in the GZ group led to an increase in the level of free carnitine in the last blood plasma samples of newborns. In general, the proposed nutrition strategy was accompanied by better indicators of physical development of children. Children who consumed more protein were transferred from the intensive care unit earlier – 10.00 (8.00; 12.00) days, against 12.00 (11.00; 16.00) days, with U = 235.00; p = 0.0024; previously discharged from the hospital -21.00 (19.00; 27.00) days, against 26.50 (22.00; 31.00) days at U = 267.00, p = 0.0109. This strategy proved to be safe, as confirmed by normal levels of phenylalanine and blood biochemical indicators at all stages of the examination of children, including urea nitrogen and creatinine.
 Conclusions. Short-term increased consumption of protein against the background of carnitine supplementation improves the results of the physical development of newborns, does not lead to deviations in the biochemical profile, and is safe.

The clinical presentation of PIT1 positive pituitary neuroendocrine tumor immunonegative for growth hormone, prolactin, and thyroid stimulating hormone with analysis of clinical and immunostaining dissociation

BackgroundPIT1 is a pituitary transcription factor that is associated with either growth hormone (GH), prolactin (PRL), or thyroid-stimulating hormone (TSH) production. However, PIT1-positive pituitary neuroendocrine tumors (PitNETs) are occasionally immunonegative for GH, PRL, and TSH. This paper describes the clinical presentation of PIT1 positive however immunonegative PitNETs. MethodsWe conducted a retrospective analysis, identifying 228 PIT1-positive PitNET patients between 2017 and 2022. Out of these, ten (4%) tested negative for GH, PRL, and TSH. Functioning PitNETs were defined as those causing hormonal excess symptoms or hormonal overproduction. ResultsAs for 10 patients immunonegative for all three hormones however PIT1-positive, the mean ( ± standard deviation) age was 46 ± 13 years with 70% women. Six patients exhibited signs of excess GH or PRL, and three had visual problems. Additionally, one patient had secondary hypothyroidism and adrenal insufficiency resulting from the mass effect. All tumors were macroadenoma, with a median volume of 2.1 cm3 (range, 0.8–17.5 cm3). Gross total resection was attained in six patients by trans-sphenoidal surgery. Postoperatively, eight patients experienced clinical improvement: three in vision, two in amenorrhea, two in headache, and one in acromegaly symptoms. Biochemical improvement was observed in six patients, with all experiencing remission in hormonal excess and one showing improvement in secondary hypothyroidism. Stereotactic radiosurgery was performed in three patients. ConclusionsPatients with functioning PitNETs may exhibit PIT1 staining without GH, PRL, or TSH staining. Hormonally active tumors exist in this patient population; therefore, close endocrine follow-up is necessary despite the lack of staining for GH, PRL, and TSH.

Abstract 16737: Explantation of LVAD in Recovered Alcohol Induced Cardiomyopathy

Durable Left Ventricular Assist Device (LVAD) is an important modality for bridge or destination therapy for patients with end-stage heart failure. However, there is a paucity of evidence guiding management for LVAD explantation in patients with sufficient myocardial recovery as this only occurs in 1-3% of cases. We present a case of a patient with LVAD placement due to alcoholic cardiomyopathy with subsequent removal of his LVAD three years later. Description of Case: A 51-year-old male with a history of alcohol induced cardiomyopathy with an LV ejection fraction of 10% s/p Heartmate II LVAD implant 3 years ago was evaluated for LVAD explantation. Over the course of one year, LVAD speed was decreased and ejection fraction (EF), cardiac output (CO) and cardiac index (CI) were monitored. Prior to explantation, the patients EF was 50% with a CO of 5.6L/min and CI 2.7 L/min/m2. Following successful explantation, a repeat echocardiogram 3 months later revealed an EF of 45%. Right heart catheterization revealed CO of 5.3L/min and CI 2.6L/min/m2. Patient was discharged on guideline directed medical therapy with continued improvement. Discussion: Mechanical, histological, and biochemical myocardial improvement has been described in LVAD recipients. There is a paucity of data to guide recovery assessment and candidacy for explantation. The 2023 ISHLT guidelines have attempted to synthesize the available data and outline the major considerations. Assessment should be done at low LVAD speeds with incorporation of data from patient’s clinical status, echocardiography, right heart catheterization, and cardiopulmonary exercise testing. Utilization of LVAD as a bridge to recovery was feasible in our patient given careful assessment of recovered cardiac function as outlined by aforementioned criteria. LVAD explantation after heart recovery remains a rare phenomenon. As access to cardiac transplantation remains limited, consistent use of guideline directed medical therapy allows for the possibility of heart recovery along with explantation. We present a case of successful and maintained myocardial recovery after LVAD explantation. Cases such as this would benefit from standardization of LVAD explantation guidelines for optimal long-term survival for patients.

Interpreting growth hormone and IGF-I results using modern assays and reference ranges for the monitoring of treatment effectiveness in acromegaly.

Standard treatment for acromegaly focuses on the achievement of target absolute levels of growth hormone (GH) and insulin-like growth factor (IGF-I). The appropriateness of these targets when measured using modern assay methods is not well defined. This paper reviews biochemical status assessed using methods available at the time and associated clinical outcomes. GH measurements were shown to provide an indication of changes in tumor size, and failure of GH suppression after glucose stimulation is associated with tumor recurrence. IGF-I levels were more closely associated with changes in symptoms and signs. Reduced GH and IGF-I concentrations were shown to be associated with increased longevity, although the degree of increase has only been analyzed for GH. Lowering of GH and IGF-I has consistently been associated with improved outcomes; however, absolute levels reported in previous studies were based on results from methods and reference ranges that are now obsolete. Applying previously described absolute thresholds as targets (e.g. "normal" IGF-I level) when using current methods is best applied to those with active acromegaly symptoms who could benefit from further lowering of biochemical markers. In asymptomatic individuals with mild IGF-I or GH elevations, targeting biochemical "normalization" would result in the need for combination pharmacotherapy in many patients without proven benefit. Measurement of both GH and IGF-I remains an essential component of diagnosis and monitoring the effectiveness of treatment in acromegaly; however, treatment goals based only on previously identified absolute thresholds are not appropriate without taking into account the assay and reference ranges being employed. Treatment goals should be individualized considering biochemical improvement from an untreated baseline, symptoms of disease, risks, burdens and costs of complex treatment regimens, comorbidities, and quality of life.

FRI425 BIUXX

Abstract Disclosure: D.M. Macedo: None. J. Casanova: None. A. Guerra: None. R. Francisco: None. Title: Hyperandrogenism due to post-menopausal ovarian stromal hyperplasia. Introduction: Severe and rapidly progressive installation of hyperandrogenism in women after menopause should be carefully investigated. Stromal hyperplasia of the ovaries, which etiology is not completely understood, is a rare and benign cause of excess androgen production. In addition to hyperandrogenism, it is usually associated with hyperinsulinism, obesity, metabolic syndrome and acanthosis nigricans. Clinical case: A 60 year old overweight female patient with a history of type 2 diabetes mellitus, dyslipidemia, polycystic ovarian syndrome and menopause at 53 years old, reported the recent onset of hirsutism on the face and back, alopecia and increased libido. The laboratory evaluation revealed: total testosterone 89.6ng/dL (<35.9), free testosterone 5.13pg/mL (<4.2), sex hormone-binding globulin 22.9nmol/L (18-144), LH 21.3mIU/mL (14-52), FSH 27.4mIU/mL (26-135) and E2 <19.0pg/mL. The remaining androgens did not show alterations and hypercortisolism was excluded. Abdominal and pelvic ultrasound was performed and revealed enlarged ovaries with homogeneous echotexture and reduced echogenicity. A pelvic MRI was also performed and showed solid lesions in both ovaries, with moderate T1 and T2 hypointensity, suspicious of bilateral androgen-producing ovarian tumors. After multidisciplinary discussion, the patient underwent total hysterectomy with bilateral oophorectomy. Histopathology was compatible with bilateral stromal hyperplasia of the ovaries. Three months after surgery, the patient presented with a reduction of the facial and back hirsutism and slight improvement in alopecia. The laboratorial evaluation revealed a marked reduction in total testosterone (18.0ng/dL) and free testosterone (1.07pg/mL). Conclusions: New-onset hyperandrogenism in postmenopausal women is very uncommon and a diagnostic challenge. After excluding iatrogenic causes, hypercortisolism or adrenal tumor, the differential diagnosis between virilizing ovarian tumor and bilateral stromal hyperplasia is difficult to establish. Although the imaging distinction is possible, the definitive diagnosis is histopathologic and total hysterectomy with bilateral oophorectomy should be performed. In this case, although MRI was suspicious of bilateral ovarian tumors, the definitive diagnosis was stromal hyperplasia of the ovaries. Three months after surgery, the patient presented marked clinical and biochemical improvement. Presentation Date: Friday, June 16, 2023

SAT538 Thyrotoxicosis in the Setting of Metastatic Poorly Differentiated Thyroid Carcinoma, a Marker of Disease Progression?

Abstract Disclosure: B.L. Chang: None. M.A. Fernandez: None. K.M. Shikuma Lee: None. Background: Thyrotoxicosis is a rare manifestation of thyroid cancer, and poorly differentiated thyroid carcinoma (PDTC) causing thyrotoxicosis has even more rarely been reported. Here, we report a case of PDTC with thyrotoxicosis developing in a previously euthyroid individual with longstanding untreated follicular neoplasm. Clinical Case: A 79-year-old veteran presented to routine endocrine follow up with new symptoms of thyrotoxicosis. Although previously euthyroid, the evaluation revealed new findings of low serum thyrotropin (TSH) (<0.01 uIU/mL, n=0.34 – 5.60 uIU/mL), elevated free thyroxine (FT4) (2.6 ng/dL, n=0.58 – 1.64 ng/dL), and high total T3 (TT3) levels (223 ng/dL, n=76 – 181 ng/dL). Thyroid stimulating immunoglobulin antibodies (TSI) were positive (214, n<140). Patient has a nine-year history of a fine needle aspiration (FNA) of a large right-sided thyroid nodule with cytology suspicious for follicular neoplasm but declined surgical removal. Thyroid uptake and scan showed heterogeneous uptake throughout the right lobe with a relative photopenic region centrally and spots of more increased activity in areas within the right lobe. The left thyroid lobe showed uniformly low uptake. PET-CT evaluation confirmed spotty FDG-avid areas within the right thyroid mass but did not show other areas of hyperactivity. Methimazole was started with clinical and biochemical improvement. Patient underwent total thyroidectomy, and histopathologic examination showed PDTC with extensive angioinvasion involving the majority of the right thyroid lobe with the left lobe containing a mix of benign thyroid tissue and PDTC fragments. Areas of hyperintensity on the uptake scan correlated to pathological PDTC locations within the right lobe. Within three weeks of thyroidectomy, patient developed recurrent hyperthyroidism. Laboratory studies showed low TSH (0.04 uIU/mL) and elevated FT4 (2 ng/dL). In contrast to pre-operative studies, repeat TSI was below the reference range. Levothyroxine (LT4) was held in anticipation of radioactive iodine therapy, but four weeks later the TSH remained suppressed. 131I was administered which showed accumulation within small thyroid remnants and a single left level three 131I-avid lymph node without other metastases. Following 131I treatment, patient returned to a euthyroid state on standard LT4. Conclusion: Hyperthyroidism has rarely been associated with PDTC, although previous reports have linked more aggressive, multifocal, and locally invasive thyroid cancers to concurrent Graves’ disease or productive bulky metastatic disease. Even without bulky metastatic disease, clinicians should be aware that hyperproductivity may indicate development of autoimmune thyrotoxicosis within PDTC. Presentation Date: Saturday, June 17, 2023

Gut ecological networks reveal associations between bacteria, exercise, and clinical profile in non-alcoholic fatty liver disease patients.

Gut microbial dysbiosis has been observed in non-alcoholic fatty liver disease (NAFLD). The beneficial impact of exercise, the recommended lifestyle change for NAFLD patients, might be mediated by the gut microbiome (GM). However, the exact taxonomic and functional signatures associated with the host's clinical and biochemical improvement during exercise in NAFLD patients have not been elucidated yet. To investigate the impact of exercise on GM and reveal GM structures associated with NAFLD improvement during exercise. Stool samples from a 12-week randomized controlled exercise study on NAFLD subjects (N = 39) were retrieved, and shotgun metagenomics was performed at baseline and endpoint. Differential correlation network and enrichment analysis were applied to characterize the GM taxonomic and functional changes during the exercise intervention and to associate GM changes with biomarkers of liver status and metabolic dysregulation. Network analysis demonstrated that exercise induced significant changes in the bacterial interactome, which were associated with waist circumference; resting metabolic rate; plasma fasting concentrations of triglyceride, glucose, insulin, and glycated hemoglobin A1c; and homeostasis model assessment for insulin resistance. Grouping the patients in the exercise group (N = 20) as responders (N = 13) and non-responders (N = 7) using their intrahepatic lipid content (IHL) change allowed us to identify bacteria consortia contributing to the levels of alanine fermentation, methanol-, creatinine-, and protocatechuate degradation and as a result to the plasma concentrations of liver injury markers alanine transaminase, gamma-glutamyl transaminase, and aspartate transaminase. We showed that even though exercise has not a significant impact on the alpha- and beta-diversity of NAFLD patients, it leads to a significant re-structuring of the gut bacteria interactome and that specific structural changes can be linked with improvements in IHL. IMPORTANCE Our study is applying a community-based approach to examine the influence of exercise on gut microbiota (GM) and discover GM structures linked with NAFLD improvements during exercise. The majority of microbiome research has focused on finding specific species that may contribute to the development of human diseases. However, we believe that complex diseases, such as NAFLD, would be more efficiently treated using consortia of species, given that bacterial functionality is based not only on its own genetic information but also on the interaction with other microorganisms. Our results revealed that exercise significantly changes the GM interaction and that structural alterations can be linked with improvements in intrahepatic lipid content and metabolic functions. We believe that the identification of these characteristics in the GM enhances the development of exercise treatment for NAFLD and will attract general interest in this field.

Clinical, hemodynamic and biochemical improvement related to left bundle branch area pacing

Clinical, hemodynamic and biochemical improvement related to left bundle branch area pacing

Alterations in the gut microbiota and the efficacy of adjuvant probiotic therapy in liver cirrhosis.

Liver cirrhosis is the end stage of various chronic liver diseases (CLDs). The gut microbiota can impact the liver environment and trigger chronic liver inflammation through the gut-liver axis. Alteration of the gut microbiota has become an effective strategy in the biological treatment of cirrhosis. Twenty-eight patients with liver cirrhosis and 16 healthy individuals were included, and fresh stool samples were collected. We analyzed changes in the gut microbiota between groups by 16S rRNA sequencing and evaluated the association between microbiota alterations and hepatic function. Additionally, 102 cirrhotic patients were retrospectively enrolled and divided into a probiotic group (n=44) and a nonprobiotic group (n=58) in addition to standard treatment for cirrhosis. Patients were monitored for hematological parameters and hepatic function during the six-month follow-up. The gut microbiota profile of patients with cirrhosis was greatly different from that of healthy individuals, presenting with significantly reduced α diversity and decreased abundance of representative SCFA-producing bacteria including Firmicutes, Coprococcus and Clostridium IV. The pathogenic bacteria Gammaproteobacteria, Veillonella, and Bacilli were greatly enriched in cirrhotic patients. Additionally, patients with decompensated cirrhosis (DCPC) had a significantly reduced abundance of Oscillibacter compared to compensated cirrhosis (CPC), which is also a SCFA-producing bacteria, and the lower Firmicutes to Bacteroidetes ratio and enhanced MDR values were also shown in DCPC patients compared to CPC patients. In addition, the abundance of Firmicutes was negatively related to hepatic function in cirrhotic patients, including the levels of ALT, AST, and DBIL. From the retrospective study, we found that biochemical improvements in alanine transaminase (ALT) and total bilirubin (TBIL) were obtained in DCPC patients who received oral probiotic therapy compared with the nonprobiotic group. Severe microbial dysbiosis existed in patients with liver cirrhosis, especially patients who reached the decompensatory stage. SCFA-producing bacteria were significantly reduced in cirrhosis. Altered gut microbiota cause changes in functional modules, which may contribute to cirrhosis progression and are associated with clinical prognosis. Adjuvant probiotic supplementation to enhance SCFA-producing bacteria can be a prospective therapy for patients with cirrhosis.

DP23 Paraprotein negative Schnitzler syndrome: a new clinical entity?

Abstract Schnitzler syndrome (SchS) is a rare autoinflammatory condition with prominent cutaneous features. The genetic basis of the condition is not understood. The Strasbourg Criteria outline the clinical diagnosis of SchS, requiring an IgM or IgG monoclonal gammopathy and an urticarial rash (Simon A, Asli B, Braun-Falco M et al. Schnitzler’s syndrome: diagnosis, treatment, and follow-up. Allergy 2013; 68:562–8). We report two cases of SchS, the first with a 5-year delay in the development of a paraprotein and the second with complete absence of a paraprotein, despite 12 years of symptoms. Case one was a 47-year-old female who attended with a 4-year history of a dusky-red urticarial rash and polyarthralgia. Inflammatory markers were persistently raised, in the absence of any identified cause. Investigations demonstrated thrombocytosis, hypocomplementaemia and an isolated elevated IgM (3.07 g L–1), with no monoclonal band. Serum free light chain κ : λ ratio was normal. The patient had a working diagnosis of hypocomplementaemic urticarial vasculitis, despite skin biopsy demonstrating a lack of fibrinoid necrosis. She failed to improve symptomatically on high-dose antihistamines, corticosteroids or azathioprine and had minimal improvement with omalizumab. Repeat serum electrophoresis identified the development of a new IgM κ paraprotein 5 years after the initial symptom onset. Interleukin (IL)-1 blockade resulted in rapid clinical and biochemical improvement. Case 2 was a 55-year-old woman with a 4-year history of recurrent urticaria. A diagnosis of urticarial vasculitis was made; skin biopsy was incongruent but displayed a neutrophilic infiltrate. She had a poor response to high-dose antihistamines and withdrew from services for 3 years. Subsequent therapy with ciclosporin, azathioprine, omalizumab, dapsone and colchicine yielded no clinical benefit. Laboratory investigations repeatedly showed elevated inflammatory markers and an elevated IgA (3.9 g L–1) in the context of inflammatory bowel disease but no IgM or IgM paraprotein. Serum free light chain κ : λ ratio was normal. Clinical suspicion of an autoinflammatory condition was high given the longstanding treatment-resistant urticaria and systemic inflammation. A trial of IL-1 blockade led to immediate clinical and biochemical resolution. This treatment was continued and has resulted in the eradication of a cumulative 12 years of symptoms. There are several reports of SchS with no monoclonal band responding to IL-1 antagonism. As these cases do not fulfil the obligatory criteria for SchS, we propose a new clinical entity, paraprotein-negative IL-1-mediated inflammatory dermatosis (PANID). It is not yet clear if PANID is a precursor to SchS, although published cases demonstrating delayed paraprotein development could support this. Clinicians should consider this diagnosis in patients with treatment-refractory urticaria and systemic inflammation.

Tracer metabolomics reveals the role of aldose reductase in glycosylation

Abnormal polyol metabolism is predominantly associated with diabetes, where excess glucose is converted to sorbitol by aldose reductase (AR). Recently, abnormal polyol metabolism has been implicated in phosphomannomutase 2 congenital disorder of glycosylation (PMM2-CDG) and an AR inhibitor, epalrestat, proposed as a potential therapy. Considering that the PMM2 enzyme is not directly involved in polyol metabolism, the increased polyol production and epalrestat's therapeutic mechanism in PMM2-CDG remained elusive. PMM2-CDG, caused by PMM2 deficiency, presents with depleted GDP-mannose and abnormal glycosylation. Here, we show that, apart from glycosylation abnormalities, PMM2 deficiency affects intracellular glucose flux, resulting in polyol increase. Targeting AR with epalrestat decreases polyols and increases GDP-mannose both in patient-derived fibroblasts and in pmm2 mutant zebrafish. Using tracer studies, we demonstrate that AR inhibition diverts glucose flux away from polyol production toward the synthesis of sugar nucleotides, and ultimately glycosylation. Finally, PMM2-CDG individuals treated with epalrestat show a clinical and biochemical improvement.