Serum Angiotensin-converting Enzyme Research Articles

493 A CASE REPORT OF SUBACUTE INFLAMMATORY HEART DISEASE WITH AN ATYPICAL ONSET

Abstract Background Inflammatory heart disease is a heterogeneous process with variegate clinical manifestations. The acute phase is characterized by a sudden injury involving cardiomyocytes, cardiac conduction system and/or pericardium, with different pathophysiological implications. Case Summary A 26-year-old previously healthy woman presented for worsening fatigue and bradycardia. The ECG at admission showed total heart block with infra-Hisian escape rhythm, heart rate was 36 bpm. She reported no history of tick bite or recent inflammatory event; body temperature was 36,8 °C. Laboratory assessment showed persistently raised troponin (28943 -> 32632 ng/l), C-reactive protein was 0,70 mg/l, white blood cells 4,86×10^3/µl, procalcitonin 0,03 µg/l, interleukin-6 was 60,5 pg/ml (n.v. <28,0) and NT-pro-BNP was 312 pg/ml. Borrelia, Salmonella, Ricketsiae, Toxoplasma screening was negative for acute infection as well as any other viral serology. Comprehensive laboratory autoimmunity assessment was negative. Echocardiography revealed normal biventricular volume and kinetics, no valvulopathies and no pericardial effusion. Coronary angiogram was normal. The cardiac magnetic resonance showed extensive oedema and contextual late gadolinium enhancement predominantly in the interventricular septum and mid segment of the anterior wall. Serum angiotensin-converting enzyme concentration was normal. Due to persistent heart block, after 5 days the patient underwent endomyocardial biopsy that showed slight oedema and mild fibrosis without lymphocytic infiltration nor histochemical findings suggestive of active myocarditis. Granulomas were absent. Viral analysis on myocardium was negative. An intermediate dose of steroids was started with a progressive restoration of 1:1 atrioventricular conduction and shortening of QRS up to incomplete right bundle branch block, hence the patient was discharged without pacemaker implantation. Discussion In heart inflammatory diseases with bradyarrhythmic onset, atrioventricular conduction may be restored with targeted therapy. Multimodality assessment is crucial in the diagnostic and therapeutic work-up of these cases.

Utility of angiotensin-converting enzyme and serum calcium levels in cutaneous sarcoidosis.

Sarcoidosis is a granulomatous disease of unknown etiology but is theorized to result from immune overactivity in the setting of an environmental or genetic trigger. It most commonly affects the lungs and lymph nodes but can affect other organ systems, with cutaneous involvement in 30% of patients. The granulomas associated with sarcoidosis lead to increased activity of angiotensin-converting enzyme (ACE) and 1α-hydroxylase resulting in an uncontrolled synthesis of 1,25-dihydroxyvitamin D3 by macrophages, along with elevated serum ACE and calcium levels. Serum ACE and calcium levels are frequently ordered when a patient is diagnosed with cutaneous sarcoidosis. However, their clinical utility in this setting remains unknown. In this retrospective chart review, we assessed serum ACE and calcium levels in 19 patients with cutaneous sarcoidosis diagnosed by histopathology without preceding evidence of systemic involvement. Serum ACE and calcium levels were also investigated as markers in the progression from mono-organ cutaneous sarcoidosis to systemic sarcoidosis. No patients with biopsy-proven cutaneous sarcoidosis had abnormal levels of serum calcium at presentation in a cohort of 17 patients at a single institution. An abnormally elevated ACE level was only seen in one of 13 patients presenting with cutaneous sarcoidosis. Our data suggest that serum ACE and calcium levels are not reliable markers of either cutaneous sarcoidosis or the progression to systemic sarcoidosis.

Serum Ace and Ace I/D Polymorphism: Risk of Type 2 Diabetes with and Without Nephropathy in Pakistani Cohort

Objective: To find serum ACE (Angiotensin converting enzyme) level and the role of ACE I/D polymorphism with T2DM (Type 2 Diabetes Mellitus) among the Pakistani cohort.
 Methods: A total of 110 diagnosed T2DM patients and 100 normotensive healthy controls with an agerange of 35-65 years were randomly selected for this study. All cases were screened for the T2DM based on random and fasting blood sugar levels and confirmed by HbA1c test. Genomic DNA was extracted from peripheral blood samples by the Salting out method and ACE I/D polymorphism was genotyped using insertion-deletion polymorphism. A serum level of ACE was also determined. All statistical analysis was conducted using SPSS 16 and all values are significant at a p-value less than 0.05. Hardy Weinberg Equilibrium (HWE) was calculated for any deviation of allele frequencies from predicted. The Chi-square test was used to evaluate the association between ACE polymorphism and the risk of diabetes. The odds ratio along with a 95% confidence interval via binary logistics regression analysis was used to find out the diabetic risk associated with ACE genotyping.
 Results: The analysis showed higher ACE levels among T2DM patients with nephropathy (mean =158 ± 38.9) and without nephropathy (mean = 128.23 ± 46.8) as compared to controls (mean = 94.4± 28.6). No significant association (÷2 = 7.402, p-value=0.116) was observed between ACE genotyping and T2DM. However, those who have DD (O.R= 2.714, 95% CI=0.943-7.809) genotype of ACE polymorphism was at risk of diabetes but the results were non-significant. However, no risk was present at the diabetic nephropathy females.Conclusion: These outcomes propose that the ACE gene may not contribute to T2DM in the Pakistanicohort. However, ACE levels were higher among T2DM with and without nephropathy patients.

A Rare Case of Cryptogenic Organizing Pneumonia with Sarcoidosis Overlap

Cryptogenic organizing pneumonia (COP) with sarcoidosis, as an overlap disease, occurs infrequently. We report a case of an elderly female, who was diagnosed as a case of COP based on radiological and histopathological evaluation. After the systemic steroid therapy, there occurred a significant fall in serum angiotensin-converting enzyme (SACE) levels, pointing toward the clinical diagnosis of sarcoidosis. This case raises the possibility of sarcoidosis as an etiology of COP in patients with a mixed spectrum of presentation.

Abstract 12625: Genome-Wide Analysis Revealed Genetic Control of the Renin-Angiotensin-Aldosterone System in the General Population

Introduction: The Renin-Angiotensin Aldosterone system (RAAS) is the major player in the long-term blood pressure (BP) regulation. The RAAS is targeted by commonly used anti-hypertensive drugs, but despite its importance, little is still known about its genetics, partially due to the technical difficulties in the quantification of the involved biomarkers. Methods: Using mass-spectrometry, we simultaneously quantified in serum equilibrium angiotensin I, angiotensin II and aldosterone on 2105 participants to the Cooperative Health Research In South Tyrol study (CHRIS), who were either normotensive or under documented anti-hypertensive drug (AHD) treatment. We derived proxies of renin activity (PRA-S= angiotensin I + angiotensin II), angiotensin-converting enzyme activity (ACE-S= angiotensin I / angiotensin II) and adrenal gland function (AA2-ratio =aldosterone/ angiotensin II). We tested association of these biomarkers with 1,085,897 SNPs imputed against a population specific whole-exome-sequencing-based panel, adjusting for age, sex, AHD, and assuming an additive genetic model using Regenie v3.1.1. Results: Study participants were 21 to 95 years old, and 52% were females. Most participants (86%) received specific AHD treatments. ACE-S was associated with variants spanning the ACE gene. The top association was seen at rs4363 (p=2.8E-18), already associated with serum ACE level, and replicating previous findings in an Asian population sample. We found strong evidence of association of angiotensin II and AA2-ratio with the stop gained rs27044 (p=8.2E-10) in the ERAP1, involved in angiotensin II degradation. We observed a borderline association between aldosterone and the synonymous rs7275 at SMARCA4/LDLR (p=5.85E-8), previously related to lipid metabolism. We also report a novel suggestive association between angiotensin I and rs2274978 in the Xaa-Pro aminopeptidase I (XPNPEP1; p=9.49E-6). Conclusions: While some results await replication in an independent cohort, findings are consistent with known physiology, and shed light on genetic background of BP regulation.

Investigation of Serum Angiotensin-Converting Enzyme (ACE) Concentration and ACE Gene Polymorphism in Patients With SARS-CoV-2 Pneumonia Admitted to the Emergency Department.

Background This study seeks to investigate the distribution of the angiotensin-converting enzyme (ACE) gene polymorphism and serum levels in patients with viral pneumonia and predict which polymorphism will lead to severe progression of the disease. Methodology The serum ACE levels and ACE gene polymorphisms were successfully evaluated with respect to subsequent viral pneumonia using records of 100 patients with viral pneumonia and 100 healthy controls. Results ACE serum concentration was statistically significantly elevated. ACE serum concentration with a cut-off value of ≥5,256.05 pg/mL had 85.3% sensitivity and 83.2% selectivity. In addition, patients with ACE genotype D/D were 0.08 times more likely to manifest severe lung involvement than those with I/I, and patients with the I/D genotype were 0.02 times more likely than their counterparts with I/I. The computed tomography findings of the patients revealed that ACE serum concentration was significantly effective in discriminating between mild and moderate-to-severe lung involvement. No significant difference was observed between the blood parameters and ACE genotype distributions. Conclusions I/D polymorphism likely affects the expression of the ACE gene and/or the function of the angiotensin I converting enzyme. The D/D genotype is associated with vessel wall thickness and higher blood pressure. Strong evidence was found between D/D and I/D genotypes in the patient cohort concerning genotypes and ACE serum concentration. Further analysis showed that ACE serum levels were more elevated in the D/D genotype compared to the I/D genotype in the patient cohort.

ODP522 Thyroid Sarcoidosis: A Rare Manifestation of Systemic Sarcoidosis

Abstract Introduction Sarcoidosis is a multisystem granulomatous disease of unknown aetiology characterized by noncaseating granulomas. Thyroid infiltration remains extremely rare. If present, it can cause diffuse goitre and rarely a solitarythyroid nodule. Almost all patients are euthyroid. Here, we report a case of systemic sarcoidosis with thyroid involvement. Case presentation A21-year-old female of Nepalese origin with past medical history of Asthma presented with painful eyes and was diagnosed with bilateral anterior uveitis. Symptoms improved with topical Dexamethasone and Cyclopentolate. A screening chest radiograph showed significant hilar adenopathy. Chest CT scan confirmed extensive mediastinal adenopathy particularly in the right paratracheal, subcarinal and hilar node suggestive of sarcoidosis. Endobronchial Ultrasound-guided Transbronchial Needle Aspiration (EBUS-TBNA) revealed non-necrotising granulomas. There was no evidence of tuberculosis on any materials obtained. TB-PCR and AFB were both negative. Further investigations showed raised serum ACE (163 units/L) with normal adjusted calcium levels and normal 24-hour urine calcium levels. During follow up, she developed palpable cervical and submandibular lymphadenopathy. Systemic examination revealed a smooth goitre and erythema nodosum. She did not have any neck pain and remained clinically euothyroid. Thyroid ultrasound showed several small microlobulated hypoechoic regions in both thyroid lobes, the largest measuring 7 mm in the right and left upper poles. Fine needle aspiration cytology revealed granulomata consistent with thyroid sarcoidosis. The thyroid MDT recommend conservative management with periodic clinical and biochemical assessment. She remains well at 6 months of follow up. Conclusion Sarcoid granulomata within the thyroid gland remains rare. This case report illustrates that in patients with known sarcoidosis, careful thyroid assessment should be carried out. Presentation: No date and time listed

Une sarcoïdose difficile à diagnostiquer

AbstractAbout a case of pulmonary granulomatosis disease first diagnosed as a tuberculosis from thoracic X ray examination; anamnesis, thoracic scanner and biological analyses established diagnosis of sarcoidosis which could be confirmed by pathological analysis of cutaneous lesions found after deep physical examination. Biological analyses showed that intern organs were also injured; corticoid therapy easily cured the disease with normalized biological values. The increase in serum angiotensin converting enzyme activity (ACE) is not specific for sarcoidosis but guides the physician toward diagnosis in this case and can follow efficacy of the therapy. Serum ACE activity is determined by spectrophotometric methods developed on biochemistry automates.

Epidemiology, clinical presentation, treatment, and outcome of neurosarcoidosis: A mono-centric retrospective study and literature review.

Neurosarcoidosis is a rare granulomatous disorder, and treatment guidelines are mainly based on retrospective studies. This retrospective study was performed to provide a detailed description of the clinical characteristics and treatment outcomes of patients with neurosarcoidosis followed at Cliniques Universitaires Saint Luc in Belgium. The second objective of our study was to perform a comparative literature review of neurosarcoidosis, with a focus on treatment outcomes with the use of TNF-α antagonist. Among 180 patients with sarcoidosis followed in our hospital, 22 patients with neurosarcoidosis were included in the final analysis. Our literature research identified 776 articles of which 35 articles met our inclusion criteria, including 1,793 patients diagnosed with neurosarcoidosis. In our cohort, the majority of patients (86%) were diagnosed with systemic sarcoidosis which was similar to that reported in the literature (83%). Serum CRP and calcemia were elevated only in 33 and 18% of patients, respectively. Serum lysozyme and angiotensin-converting enzyme were elevated in 79 and 16% of patients, respectively. Lumbar puncture and CSF fluid analysis were performed in 15/22 patients and were abnormal in all patients. Brain MRI was performed in 21/22 patients and showed abnormalities in 16 patients consisting of parenchymal lesions in 63%, hypothalamic-pituitary axis lesions in 38%, and meningeal enhancement in 31%. In both cohort patients, methotrexate was the most frequently used treatment (>45% of cases) with a favorable outcome in an average of 50% of patients. A TNF-α antagonist was administered in 9% of patients in our cohort and in 27% of patients in the literature review. The proportion of favorable outcomes in literature research was significantly higher in patients treated with TNF-α antagonists compared to methotrexate (p < 0.0001), mycophenolate mofetil (p < 0.0001), or azathioprine (p < 0.0001). The results of our cohort and literature review confirm that neurosarcoidosis occurred most frequently in the context of systemic sarcoidosis. Methotrexate is the most frequent second-line therapy. The effectiveness of therapy with TNF-α antagonists is well-demonstrated and associated with a better outcome. Their earlier use during the disease course among aggressive and/or refractory neurosarcoidosis should be considered.

Clinical usefulness of serum angiotensin converting enzyme in silicosis

IntroductionSilicosis is an irreversible and incurable disease. Preventive measures to eliminate exposure are the only effective way to reduce morbidity and mortality. In such situations, having a biomarker for early diagnosis or to predict evolution would be very useful in order to improve control of the disease. The elevation of serum angiotensin-converting enzyme (sACE) in silicosis has been described in previous studies, although its relationship with severity and prognosis is not clear. AimsTo determine the levels of sACE in a cohort of patients with exposure to silica dust with and without silicosis, and to assess their impact on the prognosis of the aforementioned patients. MethodProspective observational study on patients treated in a silicosis clinic from 2009 to 2018. sACE levels and pulmonary function tests were performed. Radiological progression was assessed in patients who had already had 2 X-rays of the thorax and / or two CT scans with at least a 1-year interval, from the time of inclusion in the study. ResultsA total of 413 cases of silicosis were confirmed, as well as 73 with exposure to silica dust but without silicosis. The mean sACE level for healthy subjects was 27.5±7.3U/L, for exposed patients without silicosis it was 49.6±24.2U/L, for simple silicosis it was 57.8±31,3U/L and for complicated silicosis it was 74.5±38.6U/L. Patients with a higher sACE generally progressed radiologically during follow-up (73.3±38.0 vs. 60.4±33.7; p<.001) and so the category of silicosis changed (73,9±38.1 vs. 62.5±34.6; p<.021). ConclusionssACE was elevated in patients with silicosis, and the greater its severity, the higher it was, which is associated with disease progression measured radiologically or as a category change of silicosis.

Serum angiotensin-converting enzyme 2 as a potential biomarker for SARS-CoV-2 infection and vaccine efficacy.

Various species of the SARS-CoV-2 host cell receptor, the angiotensin-converting enzyme 2 (ACE2), are present in serum, which may result from virus entry and subsequent proteolytic processing of the membrane receptor. We have recently demonstrated changes of particular ACE2 species in virus infected humans, either cleaved fragments or circulating full-length species. Here, we further explore the potential of serum ACE2 as a biomarker to test SARS-CoV-2 infection and vaccine efficacy in virus susceptible transgenic K18-hACE2 mice expressing human ACE2. First, in serum samples derived from K18-hACE2 mice challenged with a lethal dose of SARS-CoV-2, we observed an increase in the levels of cleaved ACE2 fragment at day 2 post-challenge, which may represent the subsequent proteolytic processing through virus entry. These elevated levels were maintained until the death of the animals at day 6 post-challenge. The circulating full-length ACE2 form displayed a sizable peak at day 4, which declined at day 6 post-challenge. Noticeably, immunization with two doses of the MVA-CoV2-S vaccine candidate prevented ACE2 cleaved changes in serum of animals challenged with a lethal dose of SARS-CoV-2. The efficacy of the MVA-CoV2-S was extended to vaccinated mice after virus re-challenge. These findings highlight that ACE2 could be a potential serum biomarker for disease progression and vaccination against SARS-CoV-2.

The importance of verifying manufacturer’s claim on specimen stability: An example in serum angiotensin converting enzyme testing

Appropriate specimen handling is integral to quality and minimizing medical errors. Clinical laboratories often rely on manufacturer’s claims for handling specimens, such as sample stability conditions. Serum angiotensin converting enzyme (ACE) is an example in which manufacturer claims and stability in the literature is limited. The purpose of this study was to demonstrate the importance to verify manufacturer’s stability using serum ACE as an example. Serum was collected from 39 healthy volunteers and ACE activity levels measured at baseline, after 4 h, 1, 3, 7 days at room temperature, after 3, 7, and 14 days refrigerated at 4 °C, after 1, 2, 4 and 8 weeks frozen at −20 °C, and after three freeze/thaw cycles. An additional 42 discarded patient serum specimens were re-analyzed after 1 or 2 weeks frozen at −20 °C. To evaluate stability performance, percent difference was compared to the clinical acceptance criteria, which was defined as a ½ total allowable error of ±10.9 %. This study found serum ACE to be stable 4 h at room temperature, 14 days refrigerated at 4 °C, up to 1 week frozen at −20 °C, and up to three freeze/thaw cycles. The preferred storage condition for serum ACE is refrigerated at 4 °C as there was minimal change in percent bias over the 14 day period. The false increase observed in samples stored frozen longer than 1 week could impact clinical decision making. The stability findings differed from manufacturer claims, highlighting the importance of verifying stability, especially for esoteric testing such as serum ACE where specimens travel long distances in varying climates to reach centralized testing locations.

ACE values in the diagnosis of sarcoidosis

Abstract Background In clinical practice, we often encounter the patients with sarcoidosis showing relatively high in the normal range of serum angiotensin-converting enzyme (ACE) value. Purpose We aimed to examine the serum ACE value of the patients with sarcoidosis and determine the new cut-off value for detecting the patients with sarcoidosis. Methods and results We retrospectively examined all 3781 subjects (51.1% men, 60.1±17.0 y.o.) in whom ACE was measured for any reasons including suspected sarcoidosis between 2009 and 2020 in our hospital. Of 293 patients with sarcoidosis, 101, 212, 84, and 88 were diagnosed as sarcoidosis in heart, lung, skin, and eyes, respectively. After excluding 477 patients taking ACE inhibitor and/or immunosuppression agent or those with any diseases affecting serum ACE levels, we analyzed 3304 subjects including 215 with sarcoidosis. Serum ACEs were 19.6 IU/L [IQR, 15.1–31.5] in the subjects with sarcoidosis and 10.7 [8.4–16.5] in those without (P&amp;lt;0.01). In ROC curve analysis of ACE for diagnosis of sarcoidosis, the cut-off point was 14.7 IU/L and the AUC was 0.865. When we used the current cut-off of 21.4 or new cut-off value of 14.7, sensitivity, specificity, PPV, NPV, and accuracy were shown in Table. Finally, they were divided into four groups based on the presence of cardiac and/or extra cardiac sarcoidosis, ACE values in Group A, B, C, and D were 17.9, 20.9, 18.6, and 10.7, respectively (Figure 1). Conclusion(s) In the current cut-off value of serum ACE, sensitivity for detecting sarcoidosis was comparatively low, though positive predictive value was low when the new-cut-off value was used in our study. Further examinations may be needed for the patients suspected sarcoidosis with relatively high ACE in the normal range. Funding Acknowledgement Type of funding sources: None.

UNCOMMON CAUSES OF RECURRENT UNILATERAL PLEURAL EFFUSIONS

UNCOMMON CAUSES OF RECURRENT UNILATERAL PLEURAL EFFUSIONS

Performance of Serum Angiotensin-Converting Enzyme in Diagnosing Sarcoidosis and Predicting the Active Status of Sarcoidosis: A Meta-Analysis.

The usefulness of serum angiotensin-converting enzyme (sACE) for diagnosing sarcoidosis and determining the active status of sarcoidosis has been reported with varying outcomes. On the basis of the majority of published data, we conducted a meta-analysis to calculate the overall predictive accuracy of sACE in sarcoidosis disease and the active status of sarcoidosis. The inclusion of related research listed in Web of Science, PubMed, Scopus, and other literature databases was assessed. SROC curves were generated to characterize the overall test results after data on sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) were combined. Publication bias was identified using Deeks’ funnel plot. Thirty-five publications with 8645 subjects met the inclusion criteria. The following are summary estimates of sACE diagnostic performance for sarcoidosis: sensitivity, 60% (95% confidence interval (CI), 52–68%); specificity, 93% (95% CI, 88–96%); PLR, 8.4 (95% CI, 5.3–13.3); NLR, 0.43 (95% CI, 0.36–0.52); and DOR, 19 (95% CI, 12–31). The area under the SROC curve (AUC) was 0.84 (95% CI, 0.80–0.87). Summary estimates for predicting the active status of sarcoidosis were as follows: sensitivity, 0.76 (95% CI, 0.61–0.87); specificity, 0.80 (95% CI, 0.64–0.90); PLR, 3.9 (95% CI, 2.1–7.3); NLR, 0.29 (95% CI, 0.17–0.49); and DOR, 13 (95% CI, 6–31). The AUC was 0.85 (95% CI, 0.82–0.88). There was no evidence of publication bias. Our meta-analysis suggests that measuring the sACE may assist in the diagnosis of sarcoidosis and predicting the active status of sarcoidosis, but the interpretation of the sACE results should be with caution. Future studies should validate our results.

OA28 A rare case of cardiac tumour in infancy mimicking sarcoidosis

Introduction/BackgroundSarcoidosis is a rare multisystemic inflammatory disorder with 2 distinct presentations in childhood. A monogenic form associated with mono-allelic mutation in NOD2 presents with the triad of uveitis, rash and arthritis in children less than 4-years (early-onset sarcoidosis). The other presentation affects older children with similar presentation to adults, with greater pulmonary and lymph node involvement. Histopathological evidence of non-caseating granulomas is essential for the diagnosis but does not exclude alternative diagnoses. We report a 17-month-old infant, who presented with atypical features suggestive of sarcoidosis, but was subsequently found to have a rare cardiac angiosarcoma driving an exaggerated granulomatous reaction.Description/MethodA previously healthy 17-month-old girl born to non-consanguineous Caucasian parents presented with recurrent fever for 3-months, associated with lethargy, weight loss and worsening anemia. Examination revealed an irritable febrile child, weight on 5th centile, with muffled heart sounds; there were no skin lesions, no lymphadenopathy, and no arthritis. Investigations showed severe anemia (Hb 46g/L), leukocytosis (WBC 24/L), thrombocytosis (662/L), high inflammatory markers (CRP >300mg/L, ESR 160mm/hr), high ferritin (600ug/L). CT thorax with cardiac angiogram revealed a large intra-atrial septal mass, extensive pulmonary nodules, bilateral hilar and mediastinal lymphadenopathy and pericardial effusion. She was managed with broad-spectrum antibiotics, blood transfusions and pericardiocentesis with endomyocardial biopsy. Extensive infectious workup, including TB from pericardial exudate, was negative. Serum angiotensin-converting enzyme was normal, with no blasts in blood film; eye examination was unremarkable. The endomyocardial biopsy was inconclusive, so underwent lung and lymph node biopsies, which were initially reported as revealing florid multiple non-necrotising granulomas, but no evidence of malignant cells. Whole-exome sequencing was performed, result pending at that stage. Differential diagnosis included malignancy, infection, immunodeficiency or autoimmune disorder including sarcoidosis, in light of histopathology. With malignancy and infection felt to be excluded, she was managed empirically for atypical sarcoidosis and treated with IV methylprednisolone 30mg/kg followed by tapering steroid and anti-TNF; IL-1 was added later. However, there was no clinical response with ongoing fever, irritability and static inflammatory markers (CRP∼300mg/L). Immunomodulating medications were subsequently stopped. Repeat chest imaging revealed progression of pulmonary findings and increasing cardiac mass. Open-heart bypass surgery with debulking of cardiac mass and further biopsies. Histopathology revealed an extremely rare primary cardiac malignant vascular tumour, angiosarcoma, with loss of SMARCB1 protein staining. Retrospective review and specific staining with SMARCB1 of initial lung biopsy subsequently confirmed that the granulomatous reaction was in response to micro-metastases of tumour throughout the lungs.Discussion/ResultsThe differential diagnosis of granulomatous disease in paediatric patients is very broad. Ultimately, the diagnosis of cancer driving and exaggerated immunological response was provided by a combination of very invasive surgical biopsy of the heart; combined with whole exome sequencing. Whole exome sequencing revealed 2 distinct genetic diagnoses which fully explained the phenotype: heterozygosity for a stop mutation in SMARCB1 (p.R158X) consistent with Rhabdoid Tumour Predisposition Syndrome Type 1; and homozygosity for the hypomorphic PRF1 p.A91V mutation explaining low (but not absent) intracellular perforin levels and exaggerated granulomatous immunological response to tumour. The rare angiosarcoma detected is scarcely reported in the literature, but entirely compatible with the type of cancer associated with RTPS1. Hypomorphic perforin mutation probably explains the exaggerated but frustrated granulomatous immunological response to tumour in this case.Key learning points/ConclusionThis case serves to remind us that granulomas can occur in response to malignancy in children. Lack of response to immunosuppression with ongoing severe systemic inflammation in this case provided an important clue to the need for more invasive diagnostic biopsies. Particular challenges relates to the time it takes to obtain genetic test results; but in this case whole-exome sequencing resolved the phenotype fully. Patients with rare and unusual presentations may have more than one genetic diagnosis, with a blending of phenotypes thereafter. Screening of other family members for the mutation associated with RTPS1 is ongoing.

Circumferential Gastric Wall Thickening With Lymphadenopathy

Question: A 78-year-old Japanese man with a history of hypertension and abdominal aortic aneurysm visited our hospital for epigastric discomfort lasting more than a week. Blood examination revealed mildly elevated white blood cell counts (9900/μL) and normal red blood cell and platelet counts. Biochemical analyses indicated no specific abnormalities except mildly elevated C-reactive protein levels (1.89 mg/dL, normal range <0.14 mg/dL). Serum tumor marker levels, including carcinoembryonic antigen and carbohydrate antigen 19-9, were within the normal ranges. Although Helicobacter pylori infection was detected via serum antibody test, he had not received eradication therapy previously. Contrast-enhanced computed tomography (CT) showed circumferential gastric wall thickening with hyperenhancement on the mucosal surface, accompanied by infrapyloric lymphadenopathies (Figure A). Minimal ascites was found around the liver and in the pelvis. On fluorodeoxyglucose (FDG) positron emission tomography–CT, the thickened gastric wall and swollen lymph nodes showed intense accumulation of FDG with a maximum standardized uptake value of 5.23 and 4.33, respectively (Figure B). Moreover, minor mucosal erosions and ulcerations on the gastric body and the antrum were observed during esophagogastroduodenoscopy (EGD) (Figure C). The distensibility of the gastric wall by CO2 insufflation was not impaired on EGD. Endoscopic mucosal biopsies were performed on the thickened gastric wall with ulcerations. What is the most likely diagnosis here, and how should these lesions be treated? Look on page 339 for the answer and see the Gastroenterology website (www.gastrojournal.org) for more information on submitting to Gastro Curbside Consult. Gastric linitis plastica (GLP), a distinct subtype of gastric cancer characterized by thickening and rigidity of the gastric wall,1Vivier-Chicoteau J. Lambert J. Coriat R. et al.Development and internal validation of a diagnostic score for gastric linitis plastica.Gastric Cancer. 2020; 23: 639-647Crossref PubMed Scopus (10) Google Scholar was primarily suspected from the imaging findings. Perigastric lymphadenopathies and ascites suggested lymph node metastases and peritoneal dissemination, reflecting the aggressive behavior of GLP.1Vivier-Chicoteau J. Lambert J. Coriat R. et al.Development and internal validation of a diagnostic score for gastric linitis plastica.Gastric Cancer. 2020; 23: 639-647Crossref PubMed Scopus (10) Google Scholar However, the biopsy obtained from the margins of the ulceration did not reveal any malignant cells suggestive of GLP. Hematoxylin and eosin (HE) staining showed infiltration of numerous histiocytes and noncaseating granuloma formation (Figure D). Because the superficial biopsy often results in inconclusive diagnosis of GLP, laparoscopic resection of the swollen infrapyloric lymph nodes was performed to obtain a more substantial amount of tissue. HE staining of the surgically resected lymph nodes showed the formation of multiple small-size epithelioid granulomas (Figure E). To determine the etiology of granuloma formation, various kinds of immunohistochemical studies were performed. Accumulation of H pylori was observed inside the granuloma of both gastric mucosa (Figure F) and lymph nodes (Figure G) with the use of H pylori–specific antibody (B0471; Dako, Denmark) whereas Epstein-Barr virus or tuberculosis was not detected by in situ hybridization or Ziehl-Neelsen staining. In addition, the possibility of gastric sarcoidosis was low because the serum angiotensin-converting enzyme level was not elevated and gastric granuloma was negative for immunostaining of monoclonal antibody against Propionibacterium acnes (D371-3; MBL, Japan).2Yamaguchi T. Costabel U. McDowell A. et al.Immunohistochemical detection of potential microbial antigens in granulomas in the diagnosis of sarcoidosis.J Clin Med. 2021; 10: 983Crossref PubMed Scopus (17) Google Scholar,3Inomata M. Ikushima S. Awano N. et al.Upper gastrointestinal sarcoidosis: report of three cases.Intern Med. 2012; 51: 1689-1694Crossref PubMed Scopus (16) Google Scholar Therefore, the diagnosis of granulomatous gastritis associated with H pylori infection was made. Successful H pylori eradication therapy with vonoprazan, amoxicillin, and clarithromycin improved his symptoms. Furthermore, gastric wall thickening on CT as well as gastric mucosal ulcerations on EGD disappeared entirely 6 months after the H pylori eradication (Figures H and I), which further verified the diagnosis. This case highlights that granulomatous gastritis associated with H pylori infection needs to be considered in the differential diagnosis when encountering H pylori–positive cases exhibiting circumferential gastric wall thickening with lymphadenopathy.

Hospitalized Patients With COVID-19 Have Higher Plasma Aldosterone-Renin Ratio and Lower ACE Activity Than Controls.

SARS-CoV-2 infects cells via the angiotensin converting enzyme 2 (ACE2) receptor, whose downstream effects "counterbalance" the classical renin angiotensin aldosterone system (RAAS). We aimed to determine to what extent circulating RAAS biomarker levels differ in persons with and without COVID-19 throughout the disease course. We measured classical (renin, aldosterone, aldosterone/renin ratio [ARR], Ang2, ACE activity) and nonclassical (ACE2, Ang1,7) RAAS biomarkers in hospitalized COVID-19 patients vs SARS-CoV-2 negative controls. We compared biomarker levels in cases with contemporaneous samples from control patients with upper respiratory symptoms and a negative SARS-CoV-2 PCR test. To assess RAAS biomarker changes during the course of COVID-19 hospitalization, we studied cases at 2 different times points ∼ 12 days apart. We employed age- and sex-adjusted generalized linear models and paired/unpaired t tests. Mean age was 51 years for both cases (31% women) and controls (50% women). ARR was higher in the first sample among hospitalized COVID-19 patients vs controls (P = 0.02). ACE activity was lower among cases at their first sample vs controls (P = <0.001). ACE2 activity, Ang 1,7, and Ang2 did not differ at the 2 COVID-19 case time points and they did not differ in COVID-19 cases vs controls. Additional adjustment for body mass index (BMI) did not change our findings. High ARR, independent of BMI, may be a risk marker for COVID-19 hospitalization. Serum ACE activity was lower in patients with COVID-19 vs controls at the beginning of their hospitalization and then increased to similar levels as controls, possibly due to lung injury, which improved with inpatient disease management.

Correlation between serum angiotensin-converting enzyme (ACE) levels and intervertebral disc degeneration

Studies have shown that the renin-angiotensin system (RAS) might play an essential role in intervertebral disc degeneration (IDD). The study aimed to investigate the relationship between serum angiotensin-converting enzyme (ACE) concentration and IDD and its predictive value for severe disc degeneration. 245 patients who came to our hospital for low back pain were recruited, and blood samples were collected for routine examination. Descriptive data and demographic parameters were collected. The cumulative grade 1 was calculated by summing up the Pfirrmann grade of all lumbar discs. ACE concentration grouping was determined via tertile split. Correlation analysis and multivariable linear regression analysis were performed to determine the relationship between ACE and IDD. The receiver's degree of disc degeneration (ROC) curve determined the ACE's predictive value. Results indicated that there was no significant difference in demographic parameters among groups. Correlation analysis and multivariate linear analysis showed that ACE was an independent risk factor for IDD. The cumulative grade 1 increased significantly with the increase in ACE concentration, which was consistent with the correlation analysis. Average Pfirrmann grade < 4 indicates mild to moderate degeneration, and grade ≥ 4 indicates severe degeneration in terms of an individual disc. From L1/2 to L5/S1, the mean plasma ACE concentration was significantly higher in the severe degeneration group than in the mild to moderate degeneration group. According to the ROC curve, the cut-off value of ACE levels was 22.5. patients with ACE > 22.5 had severe degeneration. The sensitivity and specificity were 0.762 and 0.521, respectively.

Microvascular capillaroscopic abnormalities and occurrence of antinuclear autoantibodies in patients with sarcoidosis

We described nailfold videocapillaroscopy (NVC) findings and estimated the prevalence of serum anti-nuclear (ANA) and extractable nuclear antigen autoantibodies (ENA) in a cohort of sarcoidosis patients, comparing them with adequate healthy controls (HCs) and with primary Raynaud’s phenomenon patients (PRPs). NVC findings were also correlated with the occurrence of autoantibodies, current treatment, laboratory parameters, variables of lung function and whole-body imaging data. Twenty-six patients with sarcoidosis were assessed through NVC, laboratory parameters, pulmonary function tests, chest-X ray and 18- fluorodeoxyglucose positron emission tomography/computed tomography. The NVC parameters and ANA/ENA dosage were recorded also in 30 PRPs and 30 HCs. Sarcoidosis patients showed a higher rate of capillary dilations and nonspecific abnormalities and a lower mean capillary absolute number than PRPs and HCs (p < 0.01 for all comparisons). The prevalence of ANA positivity was higher in patients with sarcoidosis compared with PRPs and HCs (p < 0.02 for both), whereas ENA positivity was detected in one sarcoidosis patient (Ro52). Among sarcoidosis patients, the mean capillary absolute number negatively correlated with the C-reactive protein concentrations and was positively associated with the forced vital capacity percentage. Instead, a negative correlation was detected between serum ACE levels and the presence of capillary dilations (all p < 0.05). Our findings suggest a microvascular involvement in sarcoidosis whose investigation by NVC might be useful for the follow-up of patients displaying RP. Autoantibody positivity in sarcoidosis might suggest autoimmune implications in the disease or the production of autoantibodies reactive to tissue damage.