Systemic Fibrosis Research Articles

Comparative transcriptomic analysis validates iPSC derived in-vitro progressive fibrosis model as a screening tool for drug discovery and development in systemic sclerosis.

Systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy, immune dysregulation, and systemic fibrosis. Research on SSc has been hindered largely by lack of relevant models to study the progressive nature of the disease and to recapitulate the cell plasticity that is observed in this disease context. Generation of models for fibrotic disease using pluripotent stem cells is important for recapitulating the heterogeneity of the fibrotic tissue and are a potential platform for screening anti-fibrotic drugs. We previously reported a novel in-vitro model for fibrosis using induced pluripotent stem cell-derived mesenchymal cells (iSCAR). Here we report the generation of a "scar-like phenotype" when iPSC derived mesenchymal cells are cultured on hydrogel that mimicks a wound healing/scarring response (iSCAR). First, we performed RNA sequencing (RNA-seq) based transcriptome profiling of iSCAR culture at 48h and 13days to characterize early and latestage scarring phenotypes. The next generation RNA-seq of these iSCAR culture at different timepoints detected expression 92% of early "scar associated" genes and 85% late "scar associated" genes, respectively. Comparative transcriptomic analysis of a gene level SSc compendium matrix to the iSCAR wound associated model revealed genes common in both data sets. Early scar formation genes showed biological processes of hypoxia (27.5%), vascular development (13.7%) and glycolysis (27.5), while late scar formation showed genes associated with senescence (22.6%). Next we show the effects of two different antifibrotic compounds to validate the utility of the model as a screening tool to study early and late-stagelate-stage fibrosis. An autotaxin inhibitor was used to validate the iSCAR late stage fibrotic model (iSCAR-T) and an antifibrotic tool screening compound of unknown mechanism (EX00015097) was used to study and validate both early (iSCAR-P) and late-stage (iSCAR-T) fibrosis in the iSCAR model.

Idiopathic Multifocal Fibrosclerosis: Mediastinal and Retroperitoneal about A Case

Multifocal fibrosclerosis is a rare entity of unknown cause, characterized by systemic fibrosis. We report the observation of a 40 year old patient, without any particular pathological history, who presents a combination of mediastinal and retroperitoneal fibrosis of idiopathic origin.

75 Juvenile systemic sclerodermas: a case report

BackgroundSystemic scleroderma (SSc) is a rare generalized connective tissue disorder of poorly understood aetiology resulting in systemic fibrosis. It affects mainly women, usually in adulthood, but can occur at any age, although it is rare in children. Its prognosis is conditioned by cardiopulmonary involvement, which is the primary cause of mortality. Some innovative therapies have improved the management of this orphan disease.We report an observation of a 14-year-old child with systemic scleroderma.ObservationChild B.Z, 14 years old, without any particular history, consulted for a Raynaud's phenomenon that had appeared 4 months earlier. Clinical examination reveals localized skin sclerosis on the face and extremities of the upper limbs (Rodnan score = 11), associated with inflammatory-type arthralgias. Biologically: SV = 38 mmH1, CRP = 87 mg/l, FAN at 1/320 and positive Anti-Scl70. Periungual capillaroscopy showed megacapillaries with altered capillary architecture. The frontal chest X-ray did not reveal any interstitial syndrome, the cardiac ultrasound was without abnormalities (no PAH). The diagnosis of SSc was retained, the patient was put on calcium channel blockers (Diltiazem at a dose of 120 mg/d) associated with dietary rules and NSAIDs on demand with good improvement.ConclusionVery few cases of juvenile SSc have been reported in the literature. Its diagnosis should be based on the same ACR-EULAR 2013 criteria as those for adults. Its prognosis is conditioned by visceral damage which must be diagnosed and treated early.

Abstract 2056: PI3Kgamma inhibition reduces inflammation and promotes survival in cancer and SARS-CoV-2

Abstract Solid tumors are characterized by extensive immune suppressive inflammation, vascular leak, fibrosis and organ damage. Similarly, SARS-CoV-2 infections induce aberrant pulmonary and systemic inflammation, vascular leak, coagulation, fibrosis and fatal organ damage. We previously demonstrated that macrophages in solid tumors strongly expressed phosphatidylinositol 3-kinase gamma (PI3Kγ), a signaling protein that coordinately controls granulocyte and monocyte trafficking to tumors as well as wound-healing-type macrophage transcription in cancer and fibrosis. We also observed that macrophages in COVID-19 lungs strongly expressed PI3Kγ. To identify therapeutic strategies to suppress COVID-19-associated inflammation, we characterized lung tissue of COVID-19 patients using multiplex immunohistochemistry and tissue transcriptomics. Lungs of deceased patients exhibited substantial infiltration by neutrophils and wound-healing macrophages, fibrosis and alveolar type II cell depletion. In animal models of lung inflammation, bacterial infections, viral infection and SARS-CoV-2 infection, PI3Kγ deletion or inhibition with the cancer therapeutic IPI-549 (eganelisib) suppressed pulmonary and systemic inflammation, reduced lung damage, and promoted survival. These studies demonstrate the essential role of PI3Kγ in inflammatory diseases as well as cancer and support the use of PI3Kγ inhibitors such as eganelisib to suppress inflammation and promote survival in pulmonary infections like SARS-CoV-2 and cancer. Citation Format: Judith A. Varner, Anghesom Ghebremedhin. PI3Kgamma inhibition reduces inflammation and promotes survival in cancer and SARS-CoV-2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2056.

Evaluation of the Abdominal Aorta and External Iliac Arteries Using Three-Dimensional Time-of-Flight, Three Dimensional Electrocardiograph-Gated Fast Spin-Echo, and Contrast-Enhanced Magnetic Resonance Angiography in Clinically Healthy Cats.

Arterial thromboembolism is associated with high morbidity and mortality rates in cats. Definitive diagnosis requires advanced imaging modalities, such as computed tomography angiography (CTA) and contrast-enhanced (CE) magnetic resonance angiography (MRA). However, CTA involves exposure to a large amount of ionized radiation, and CE-MRA can cause systemic nephrogenic fibrosis. Non-contrast-enhanced (NE) MRA can help accurately diagnose vascular lesions without such limitations. In this study, we evaluated the ability of NE-MRA using three-dimensional electrocardiograph-gated fast spin-echo (3D ECG-FSE) and 3D time-of-flight (3D TOF) imaging to visualize the aorta and external iliac arteries in clinically healthy cats and compared the results with those obtained using CE-MRA. All 11 cats underwent 3D ECG-FSE, 3D TOF, and CE-MRA sequences. Relative signal intensity (rSI) for quantitative image analysis and image quality scores (IQS) for qualitative image analysis were assessed; the rSI values based on the 3D TOF evaluations were significantly lower than those obtained using 3D ECG-FSE (aorta 3D TOF: 0.57 ± 0.06, aorta 3D ECG-FSE: 0.83 ± 0.06, P < 0.001; external iliac arteries 3D TOF: 0.45 ± 0.06, external iliac arteries 3D ECG-FSE:0.80 ± 0.05, P < 0.001) and similar to those obtained using CE-MRA (aorta: 0.58 ± 0.05, external iliac arteries: 0.57 ± 0.03). Moreover, IQS obtained using 3D TOF were significantly higher than those obtained using 3D ECG-FSE (aorta 3D TOF: 3.95 ± 0.15, aorta 3D ECG-FSE: 2.32 ± 0.60, P < 0.001; external iliac arteries 3D ECG-FSE: 3.98 ± 0.08, external iliac arteries 3D ECG-FSE: 2.23 ± 0.56, P < 0.001) and similar to those obtained using CE-MRA (aorta: 3.61 ± 0.41, external iliac arteries: 3.57 ± 0.41). Thus, 3D TOF is more suitable and produces consistent image quality for visualizing the aorta and external iliac arteries in clinically healthy cats and this will be of great help in the diagnosis of FATE.

Progressive multifocal fibrosing neuropathy: description of a novel disease

Entrapment peripheral neuropathies are clinically characterized by sensory impairment and motor deficits. They are usually caused by mechanical injuries, but they are also a frequent manifestation of metabolic diseases, toxic agent exposure, or systemic fibrotic disorders. Here we describe the clinical, radiological, and histopathological features of a novel progressive fibrotic disorder characterized by progressive multifocal fibrosing neuropathy. We identified two patients who presented with severe and progressive peripheral neuropathic symptoms sequentially affecting multiple sites. These patients presented with severe and progressive multifocal, sequentially additive peripheral neuropathic symptoms. Extensive nerve conduction and radiological studies showed the sequential development of multifocal motor and sensory peripheral neuropathy in the absence of any exposure to known infectious, inflammatory, or fibrotic triggers and the lack of family history of compression neuropathies. Extensive clinical and laboratory test evaluation failed to support the diagnosis of any primary inflammatory or genetic peripheral neuropathy and there was no evidence of any systemic fibrosing disorder including Systemic Sclerosis, lacking cutaneous fibrotic changes and cardiopulmonary abnormalities. The clinical course was progressive with sequential development of motor and sensory deficits of upper and lower extremities displaying proximal predominance. Histopathological study of tissues obtained during nerve release surgeries showed severe perineural fibrosis with marked accumulation of thick collagen bundles encroaching the peripheral nerves. There was no evidence of vasculitic, inflammatory, or vascular fibroproliferative lesions. We suggest that the clinical findings described here represent a previously undescribed fibrotic disorder affecting peripheral nerves, and we propose the descriptive term "Progressive Multifocal Fibrosing Neuropathy" to refer to this novel disorder. Despite the inherent limitations of this early description, we hope this is would contribute to the identification of additional cases.

Een harde schildkliermassa is niet altijd maligne

A hard thyroid mass: not always a malignancy In this article, the medical history of a patient with a hard mass at the thyroid and hyperthyroidism secondary to Riedel’s thyroiditis is presented. This case report shows an unusual course with a relapse, until know described in only 4 other published case reports. Riedel’s thyroiditis, also known as Riedel’s struma, is a rare invasive fibrous thyroiditis with a prevalence of 1 per 100,000 people and a male to female ratio of 1/4. Classically, it presents as a stone-like, non-tender thyroid mass with obstructive symptoms such as dyspnea, dysphagia and hoarseness as the structures surrounding the thyroid are involved. Its aetiology is unknown, but it is suggested to be part of a systemic fibrosing disorder. Thyroid dysfunction is possible, mainly hypothyroidism secondary to invasion of the normal thyroid tissue. Ultrasound findings cannot differentiate with anaplastic thyroid carcinoma, a malignancy with an unfavourable prognosis. The diagnosis is based on biopsy findings and the presence of extrathyroidal expansion of the mass. There is no standardized treatment for Riedel’s thyroiditis due to the rarity of the disease. Glucocorticoids are the mainstay of the medical treatment. Surgery is indicated only to relieve compressive symptoms.

Alstrom's Syndrome: An Experience of Tertiary Care Center.

Alstrom's syndrome (AS) is an autosomal recessively inherited multisystemic disorder that falls under the umbrella of ciliopathy. It is characterized by poor vision, hearing impairment, cardiomyopathy, childhood obesity, diabetes mellitus type 2, dyslipidemia, pulmonary, hepatic, and renal failure besides systemic fibrosis. Biallelic pathogenic variants in ALMS1 gene cause AS. Retrospective study (1990-2017) included 12 Saudi patients with AS based on their phenotype, biochemical markers, and genotype. The study was approved by Fisal Specialist Hospital and Research Centre, Riyadh (RAC number 2131129) on October 2, 2012. This study showed clinical and genetic heterogeneity; six patients showed a founder mutation (IVS18-2A > T in exon 19), whereas six others showed private mutations. AS in Saudi Arabia is underdiagnosed probably because of its variable clinical manifestations. We report 12 Saudi patients with AS to enhance the awareness about this syndrome.

Should Estimated Glomerular Filtration Rate Be Adjusted for Race?

Should Estimated Glomerular Filtration Rate Be Adjusted for Race?

Assessment of the structural and functional characteristics of human mesenchymal stem cells associated with a prolonged exposure of morphine

The discovery of the expression of opioid receptors in the skin and their role in orchestrating the process of tissue repair gave rise to questions regarding the potential effects of clinical morphine treatment in wound healing. Although short term treatment was reported to improve tissue regeneration, in vivo chronic administration was associated to an impairment of the physiological healing process and systemic fibrosis. Human mesenchymal stem cells (hMSCs) play a fundamental role in tissue regeneration. In this regard, acute morphine exposition was recently reported to impact negatively on the functional characteristics of hMSCs, but little is currently known about its long-term effects. To determine how a prolonged treatment could impair their functional characteristics, we exposed hMSCs to increasing morphine concentrations respectively for nine and eighteen days, evaluating in particular the fibrogenic potential exerted by the long-term exposition. Our results showed a time dependent cell viability decline, and conditions compatible with a cellular senescent state. Ultrastructural and protein expression analysis were indicative of increased autophagy, suggesting a relation to a detoxification activity. In addition, the enhanced transcription observed for the genes involved in the synthesis and regulation of type I collagen suggested the possibility that a prolonged morphine treatment might exert its fibrotic potential risk, even involving the hMSCs.

Therapeutic Approaches Targeting Proteostasis in Kidney Disease and Fibrosis.

Pathological insults usually disturb the folding capacity of cellular proteins and lead to the accumulation of misfolded proteins in the endoplasmic reticulum (ER), which leads to so-called “ER stress”. Increasing evidence indicates that ER stress acts as a trigger factor for the development and progression of many kidney diseases. The unfolded protein responses (UPRs), a set of molecular signals that resume proteostasis under ER stress, are thought to restore the adaptive process in chronic kidney disease (CKD) and renal fibrosis. Furthermore, the idea of targeting UPRs for CKD treatment has been well discussed in the past decade. This review summarizes the up-to-date literature regarding studies on the relationship between the UPRs, systemic fibrosis, and renal diseases. We also address the potential therapeutic possibilities of renal diseases based on the modulation of UPRs and ER proteostasis. Finally, we list some of the current UPR modulators and their therapeutic potentials.

Alström syndrome: an ultra-rare monogenic disorder as a model for insulin resistance, type 2 diabetes mellitus and obesity.

Alström syndrome (ALMS) is a monogenic ultra-rare disorder with a prevalence of one per million inhabitants caused by pathogenic variants of ALMS1 gene. ALMS1 is located on chromosome 2p13, spans 23 exons and encodes a predicted 461.2-kDa protein of 4169 amino acids. The infantile cone-rod dystrophy with nystagmus and severe visual impairment is the earliest and most consistent clinical manifestation of ALMS. In addition, infantile transient cardiomyopathy, early childhood obesity with hyperphagia, deafness, insulin resistance (IR), type 2 diabetes mellitus (T2DM), systemic fibrosis and progressive renal or liver dysfunction are common findings. ALMS1 encodes a large ubiquitously expressed protein that is associated with the centrosome and the basal body of primary cilium. The localisation of ALMS1 to the ciliary basal body suggests its contribution to ciliogenesis and/or normal ciliary function, or centriolar stability. ALMS1 regulate glucose transport through the actin cytoskeleton, which plays an important role in insulin-stimulated GLUT4 transport. Both extreme IR and β-cell failure are the two determinant factors responsible for the development of glucose metabolism alterations in ALMS. Currently, there is no known cure for ALMS other than managing the underlying systemic diseases. When possible, individuals with ALMS and families should be referred to a centre of expertise and followed by a multidisciplinary team. Lifestyle modification, aerobic exercise and dietary induced weight loss are highly recommended as primary treatment for ALMS patients with T2DM and obesity. Managing a rare disease requires not only medical care but also a support network including patient associations.

Spleen elastography in patients with Systemic sclerosis.

Systemic sclerosis (SSc) is an autoimmune inflammatory connective tissue disease. It is characterized by varying degrees of fibrosis of the skin and internal organs. Tissue fibrosis is the finalphase of a complex biological process of immune activation and vascular damage. The spleen is one of the organs thought to be involved in a systemic fibrosing process. Yet, there is a lack of research that provides evidence about splenic involvement in patients with SSc through objective instrumental techniques. Ultrasound elastography is a modern method which detects changes in the stiffness and elasticity of different organs. To assess the elasticity and stiffness of the spleen in healthy subjectsandpatients with SSc, the study included 34 patients with SSc and 35 healthy volunteers. Point SWE spleen elastography was performed on all participants in the two study groups through an Esaote MyLab 9 eXP with a C1-8 iQ appleprobe transducer. The mean age in the SSc patient group was 47.35 ± 11.48years vs. 46.20 ± 14.55years in the healthy controls, with no significant age difference, p = 0.717. The mean Body Mass Index (BMI) in the SSc patient group was 22.42 ± 2.12kg/m2 vs. 24.23 ± 4.29kg/m2 in the healthy control group with no significant difference, p = 0.410. Among the SSc patients, 18(53%) were with dcSSc and 16 (47%) with lcSSc. The mean disease duration was 59 ± 28months, ranging between 18 and 118months. Spleen stiffness median was significantly higher in the SSc patient group (3.19m/s) in comparison with the healthy controls (2.40m/s), p < 0.001. Spleen size was normally distributed and did not differ significantly between the SSc patients (105.84 ± 7.87mm) and the healthy controls (104.16 ± 8.99mm), p = 0.410. A significantly higher mean of spleen stiffness was observed in the dcSSc patients (3.38 ± 0.20m/s) in comparison with the lcSSc group (2.81 ± 0.38m/s), p < 0.001. Spleen size did not show a significant association with the type of SSc. Spleen size in the dcSSc subgroup had a mean value of 103.45 ± 5.56mm vs. 108.51 ± 9.30 in the lcSSc subgroup, p = 0.071. pSWE is an objective, reliable, and easy-to-implement method for detecting early fibrous changes in the spleen in patients with SSc. A good approach in patients with SSc could be the search for similar processes in other internal organs, such as the liver and thyroid gland.

Chemical exposure-induced systemic fibrosing disorders: Novel insights into systemic sclerosis etiology and pathogenesis

Numerous drugs and chemical substances are capable of inducing exaggerated tissue fibrotic responses. The vast majority of these agents cause localized fibrotic tissue reactions or fibrosis confined to specific organs. Although much less frequent, chemically-induced systemic fibrotic disorders have been described, sometimes occurring as temporally confined outbreaks. These include the Toxic Oil Syndrome (TOS), the Eosinophilia-Myalgia Syndrome (EMS), and Nephrogenic Systemic Fibrosis (NSF). Although each of these disorders displays some unique characteristics, they all share crucial features with Systemic Sclerosis (SSc), the prototypic idiopathic systemic fibrotic disease, including vasculopathy, chronic inflammatory cell infiltration of affected tissues, and cutaneous and visceral tissue fibrosis. The study of the mechanisms and molecular alterations involved in the development of the chemically-induced systemic fibrotic disorders has provided valuable clues that may allow elucidation of SSc etiology and pathogenesis. Here, we review relevant aspects of the TOS, EMS, and NSF epidemic outbreaks of chemically-induced systemic fibrosing disorders that provide strong support to the hypothesis that SSc is caused by a toxic or biological agent that following its internalization by endothelial cells induces in genetically predisposed individuals a series of molecular alterations that result in the development of SSc clinical and pathological alterations.

O3-020 Ultrasound analysis of skeletal muscle fibrosis in patients with systemic fibrosis

O3-020 Ultrasound analysis of skeletal muscle fibrosis in patients with systemic fibrosis

A very early diagnosis of Alstr\u04e7m syndrome by next generation sequencing

BackgroundAlström syndrome is a rare recessively inherited disorder caused by variants in the ALMS1 gene. It is characterized by multiple organ dysfunction, including cone-rod retinal dystrophy, dilated cardiomyopathy, hearing loss, obesity, insulin resistance, hyperinsulinemia, type 2 diabetes mellitus and systemic fibrosis. Heterogeneity and age-dependent development of clinical manifestations make it difficult to obtain a clear diagnosis, especially in pediatric patients.Case presentationHere we report the case of a girl with Alström syndrome. Genetic examination was proposed at age 22 months when suspected macular degeneration was the only major finding. Next generation sequencing of a panel of genes linked to eye-related pathologies revealed two compound heterozygous variants in the ALMS1 gene. Frameshift variants c.1196_1202del, p.(Thr399Lysfs*11), rs761292021 and c.11310_11313del, (p.Glu3771Trpfs*18), rs747272625 were detected in exons 5 and 16, respectively. Both variants cause frameshifts and generation of a premature stop-codon that probably leads to mRNA nonsense-mediated decay. Validation and segregation of ALMS1 variants were confirmed by Sanger sequencing.ConclusionsGenetic testing makes it possible, even in childhood, to increase the number of correct diagnoses of patients who have ambiguous phenotypes caused by rare genetic variants. The development of high-throughput sequencing technologies offers an exceptionally valuable screening tool for clear genetic diagnoses and ensures early multidisciplinary management and treatment of the emerging symptoms.

A new nucleosomic-based model to identify and diagnose SSc-ILD

BackgroundSystemic sclerosis (SSc) is a rare connective tissue disease associated with rapid evolving interstitial lung disease (SSc-ILD), driving its mortality. Specific biomarkers associated with the evolution of the lung disease are highly needed. We aimed to identify specific biomarkers of SSc-ILD to predict the evolution of the disease. Nucleosomes are stable DNA/protein complexes that are shed into the blood stream making them ideal candidates for biomarkers.MethodsWe studied circulating cell-free nucleosomes (cf-nucleosomes) in SSc patients, 31 with ILD (SSc-ILD) and 67 without ILD. We analyzed plasma levels for cf-nucleosomes and investigated whether global circulating nucleosome levels in association with or without other biomarkers of interest for systemic sclerosis or lung fibrosis (e.g., serum growth factors: IGFBP-1 and the MMP enzyme: MMP-9), could be suitable potential biomarkers for the correct identification of SSc-ILD disease.ResultsWe found that H3.1 nucleosome levels were significantly higher in patients with SSc-ILD compared SSc patients without ILD (p < 0.05) and levels of MMP-9 were significantly increased in patients with SSc-ILD compared to SSc patients without ILD (p < 0.05). Conversely, IGFBP-1 was significantly reduced in patients with SSc-ILD compared to SSc without ILD (p < 0.001). The combination of cf-nucleosomes H3.1 coupled to MMP-9 and IGFBP-1 increased the sensitivity for the differential detection of SSc-ILD. High levels of accuracy were reached with this combined model: its performances are strong with 68.4% of positive predictive value and 77.2% of negative predictive value for 90% of specificity. With our model, we identified a significant negative correlation with FVC % pred (r = −0.22) and TLC % pred (r = −0.31). The value of our model at T1 (baseline) has a predictive power over the Rodnan score at T2 (after 6-18 months), showed by a significant linear regression with R2 = 19% (p = 0.013). We identified in the sole group of SSc-ILD patients a significant linear regression with a R2 = 54.4% with the variation of DLCO between T1 and T2 (p < 0.05).ConclusionIn our study, we identified a new blood-based model with nucleosomic biomarker in order to diagnose SSc-ILD in a SSc cohort. This model is correlated with TLC and FVC at baseline and predictive of the skin evolution and the DLCO. Further longitudinal exploration studies should be performed in order to evaluate the potential of such diagnostic and predictive model.

1747-P: MicroRNA-30a Exerts Antifibrotic Effects in Subcutaneous White Adipose Tissue to Preserve Insulin Sensitivity in Obesity

White adipose tissue (WAT) is an endocrine organ that dynamically expands and contracts to meet the metabolic demands of the organism. However, prolonged excessive caloric intake overwhelms WAT depots, resulting in peripheral fat deposition, systemic glucose dysregulation, tissue fibrosis, insulin resistance, and type 2 diabetes mellitus. The chronic triggers that degrade WAT function remain undefined, hindering the development of effective strategies to treat obesity and prevent its co-morbidities. We have identified a microRNA, miR-30a, that potently stimulates subcutaneous adipose tissue metabolic flexibility and enhances systemic insulin sensitivity. In follow-up studies, we created a genetically engineered mouse model to conclusively show miR-30a expression in white adipocytes is antidiabetic. Obese mice modified to express miR-30a at elevated levels in adipose tissues maintain insulin sensitivity coupled with reduced hepatic steatosis. Proteomic profiling indicated that miR-30a targets Plasminogen Activator Inhibitor-1 (PAI-1) to limit pro-fibrotic programs that would otherwise restrict subcutaneous WAT expansion and decrease insulin sensitivity. While visceral WAT depots remain a site of significant fibrosis in mice, subcutaneous WAT fibrosis is epidemiologically linked to metabolic disease risk in adult humans. In obese humans, miR-30a expression negatively correlates with PAI-1 levels in subcutaneous WAT, supporting an anti-fibrotic role for miR-30a that ultimately defends insulin sensitivity. Collectively, our observations linking miR-30a expression to insulin sensitivity suggest a new method that restores WAT homeostasis. Disclosure N. Chernis: None. P. Saha: None. J.B. Felix: None. P.M. Masschelin: None. L. Lian: None. A. Cox: None. K. Kim: None. H. Wu: None. S.M. Hartig: None. Funding American Diabetes Association (1-18-IBS-105 to S.M.H.); National Institutes of Health (R01DK114356)

SUN-LB84 Riedel’s Thyroiditis: A Diagnostic and Therapeutic Challenge

Background: Riedel’s thyroiditis is a rare thyroid pathology which presents a challenge for clinicians to diagnose and treat. Etiology remains largely unknown, although data suggests an association with Hashimoto thyroiditis, systemic fibrosis, and IgG-4 related systemic disease. Presentation of Riedel’s thyroiditis can mimic malignant thyroid neoplasm, lymphoma, or a fibrous variant of Hashimoto thyroiditis. Due to its rarity, there is no consensus on the treatment. Clinical case: A 36-year old woman presented with a two-month history of gradually progressing neck swelling. She developed associated neck pain, decreased range of motion, hoarseness, and dysphagia, without difficulty breathing. One year prior to presentation, she had been diagnosed with hypothyroidism. She did not have a family or personal history of thyroid malignancy, however, she lived near Chernobyl during her childhood. On exam, the anterior and lateral neck was hard and enlarged, but nontender. The neck range of motion was diminished. The initial ultrasound of the thyroid demonstrated asymmetrically enlarged heterogenous diffusely nodular right thyroid and isthmus measuring 1.9cm. A CT of the chest with contrast showed diffusely enlarged thyroid extending superiorly beyond the image with mild tracheal displacement. Initial laboratory results included TSH of 17.40 uU/ml (ref: 0.35-4.94 uU/ml), free T4 of 1.06 ng/dl (ref: 0.61-1.82 ng/dl). She had a significantly increased thyroid autoantibodies (Anti-TPO >700 IU/ml with ref: 0.0-9.0 IU/ml, Anti-TG >2000 IU/ml with ref: 0.0-4.0 IU/ml). PTH and calcium were normal, and calcitonin was low. In the interim, the patient was evaluated by ENT without evidence of airway compromise. She underwent a core biopsy of the right thyroid lobe which demonstrated dense fibrous connective tissue mixed with mature lymphocytes. Pathology and immunostaining results were suggestive of Riedel’s thyroiditis. The patient was started on prednisone 60mg daily, which she tolerated for 6 weeks. Due to side effects, prednisone dose was titrated down and tamoxifen was added. Over the following 6 months, compressive symptoms resolved, and the ultrasound showed a significant decrease in the thyroid size. TSH normalized with thyroid hormone replacement. To date, she is asymptomatic and continues on tamoxifen and low dose prednisone without evidence of progression. Conclusion: Riedel’s thyroiditis is a rare condition that can progress into a medical emergency and should be suspected in patients presenting with a thyroid mass. Clinical awareness of Riedel’s symptomatology and laboratory findings should enhance our ability to distinguish and make the diagnosis. Instituting effective treatment that results in the improvement of symptoms and reduction in thyroid size can be challenging due to possible poor response or development of side effects.

The kidney urea cycle is perturbed by gadolinium‐based contrast agent treatment

IntroductionGadolinium‐based contrast agents (GBCAs) are used extensively in magnetic resonance imaging. GBCA administration causes systemic fibrosis and long‐term retention of gadolinium in every vital (and non‐vital) organ, including the brain. Gadolinium‐based contrast agents are metabolic disruptors. GBCA administration leads to hyperlipidemia, insulin resistance, and renal disease on par of that induced by high fat diet‐induced experimental obesity (Do C et al, Toxicol Appl Pharmacol 2019 Jul 15;375: 32–45). Gadolinium‐based contrast agents induce glycolytic switching in renal cortex similar to that induced by a high fat diet. The urea cycle is requisite for urinary concentration in the mammal and for elimination of nitrogenous waste. Because high fat diet can also alter the urea cycle, we investigated the impact of gadolinium‐based contrast agent treatment on the urea cycle using metabolomic data.MethodsWild‐type C57/BL6 mice were randomized by age and weight into either a 60% saturated fat diet (20% protein, 20% carbohydrate) ad libitum (n = 20) or control chow (n = 20) for 20 weeks. At Week 17 groups were then sub‐randomized into untreated (n = 10) or GBCA‐treated (n = 10) (Omniscan, 2.5mmol/kg, intraperitoneally) subgroups for the remaining 4 weeks. Kidneys were isolated from mice and then snap frozen in liquid nitrogen. Metabolites were profiled by liquid chromatography‐mass spectrometry (Metabolon, Morrisville, NC). Comparisons were performed by two‐way ANOVA with post‐hoc Tukey HSD.ResultsGBCA treatment (P ≤ 0.05) reduced citrulline relative to the non‐treated group. GBCA treatment decreased aspartate relative to no treatment (P ≤ 0.001). Although high fat diet increased renal aspartate, the effect was reduced by the combination with gadolinium‐based contrast agent. Arginosuccinate was reduced by high fat diet with respect to the control (with similar trends for gadolinium treatment and the combination). Fumarate (also a tricarboxylic acid cycle metabolite) was greatly reduced by high fat diet and the combination with gadolinium‐based contrast agents (P &lt; 0.0015 and P &lt; 0.05, respectively). Although there was a trend for gadolinium to reduce urea levels relative to control, this effect of gadolinium was reversed in the setting of high fat diet (P &lt; 0.005).ConclusionThese studies have been instrumental in defining the metabolic impact of GBCAs. Our results imply that high fat diet activates argininosuccinate lyase (thereby increasing L‐arginine). Gadolinium‐induced suppression of citrulline is either suppression of arginosuccinate synthetase or an increase of ornithine transcarbamoylase. The fact that gadolinium‐based contrast agents impact the same metabolic pathway as an experimental high fat diet suggest that there are physiologic disruptions (potentially pathologic) that will be aggravated by the combination, and that metabolic syndrome is a risk factor for gadolinium‐induced disease.Support or Funding InformationThe research was funded by the Veterans Administration Merit Award (I01 BX001958, BW); the National Institutes of Health Grant R01 DK‐102085 (BW); and the DCI/Kidney Institute of New Mexico.