Fibrosis In Women Research Articles

Liver fibrosis prediction models in a population of Latina and White women.

Point-of-care tools to assess advanced liver fibrosis, including the NFS, BARD, FIB-4, and APRI, are of major interest due to their noninvasive nature. However, these tools have not been investigated extensively in the Latina population. Given that the highest rate of NAFLD in Latinos and the most severe presentation of non-alcoholic fatty liver disease (NAFLD) is more common in women, we hypothesize that ethnicity may play a role in predicting liver fibrosis, particularly in women. We determined whether ethnicity alone or in association with other parameters can predict the severity of fibrosis in women with NAFLD when included in four tools. We retrospectively included 562 Latina and 133 White Caucasian women with a history of NAFLD. Associations between ethnicity and liver fibrosis severity using the four fibrosis predictor models were studied using backward selection multinomial logistic regression. Latina women compared to White showed lower body mass index (p < 0.001), higher HbA1c (p < 0.001), lower prevalence of bariatric surgery (p < 0.001), lower likelihood to smoke (p = 0.003), and higher prevalence of chronic kidney disease stages 3-5 (p = 0.01). Some clinical variables were associated with fibrosis but not univocally in each tool. We did not find differences in the outcome of the four models when holding all other factors and examining ethnicity alone between Latina and White women. Although we did not include data on liver histology, this is the first study examining the role of ethnicity in predicting the severity of fibrosis using established noninvasive scores and documenting no association between Latina ethnicity and the severity of fibrosis in women with NAFLD.

Angiotensin II Receptor Blockers Are Associated With Reduced Valvular Fibrosis in Women With Aortic Stenosis

BackgroundAngiotensin receptor blockers (ARBs) may slow down the progression of aortic stenosis (AS) through their antifibrotic effect. Women present more valvular fibrosis than men, so ARBs may have more effect in females. Our aim was to assess the impact of ARBs on the remodelling of the aortic valve in men and women. MethodsWe included patients who had an aortic valve replacement with or without coronary bypass grafting from 2006 to 2013. Patients with missing echocardiographic or histologic data were excluded. Warren-Yong and fibrosis scores of the explanted valves were performed. Patients were divided into 4 phenotypes according to their Warren-Yong and fibrosis scores: mild calcification/fibrosis, severe calcification/fibrosis group, predominant fibrosis group, predominant calcification group. ResultsAmong the 1321 included patients, the vast majority (89%) has severe AS. Patients in the predominant fibrosis group, compared with the predominant calcium group, were more often female (39% vs 31%; P = 0.008) with bicuspid valves (44% vs 34%; P = 0.002), and less often used ARBs (25% vs 30%; P = 0.046). Female sex was independently associated with being in the predominant fibrosis group (odds ratio 1.45, 95% confidence interval 1.08-1.95; P = 0.01), with a significant interaction between female sex and ARBs. Women taking ARBs compared with women not taking ARBs had significantly lower fibrosis scores (P < 0.001). This difference was not seen in men. ConclusionsIn this large series of patients with moderate-severe AS, among the women there was a negative association between intake of ARBs and valvular fibrosis. Thus, the possible effects of ARBs may be sex specific, with a larger therapeutic role in women.

P9: Teaching Health Disparities as Regards Cardiopulmonary Support Technologies for Underepresented/ Underserved Patients

Background: There is a growing interest in addressing health care disparities faced by underrepresented/ underserved (U/U) populations across all fields of medicine. To that end, my goal was to introduce to the undergraduate (UG) and graduate (G) bioengineering classes that I teach the challenges faced by U/U patients as regards state-of-the art cardiopulonary support technologies (CPST) for treatment of end-stage cardiac or pulmonary failure. Methods: At the University of Pittsburgh (UoP) I teach two separate UG artificial organs (AO) classes; one class focuses on cardiac assist devices and the other on pulmonary assist devices. I also teach the cardiac assist module for a G cardiovasuclar organ replacement class. Through a long-standing NSF-funded collaboration with North Carolina Agricultural and Technical State University (Greensboro, NC), a Historically Black College and University (HBCU), I also teach my AO classes to NCAT students. The NCAT courses are taught remotely (via ZOOM). For the past several years, the term projects for my UG and G artificial organs classes at UoP and NCAT have focused on i) investigating health inequities/ disparities in CPST as applied to U/U patients; and, ii) proposing innovative improvements to current CPST that benefit, particularly, U/U patients. Students are asked to address the following in their term papers and class PPT presentations: 1) current state-of-the art in CPST; 2) limitations of current CPST as applied to U/U patients; 3) unmet clinical needs for U/U patients; 4) the feasibility of the proposed innovative improvements from a product specification, regulatory and societal viewpoint. Results: Students identified numerous reference materials that highlight the inequities/ disparities that U/U patients face. The American Heart Association, the CDC and NHLBI all maintain detailed epidemiological information related to the term project topic. There also exists a plethora of peer-reviewed published articles in this regard; a few examples being, Frech et al, “Ventricular Assist Device Technology and Black-White Disparities on the Heart Transplant Wait List.” Progress in Transplantation 2021; 31(1): 80-87; Nyak et al, “Understanding the Complexity of Heart Failure Risk and Treatment in Black Patients.” Circulation Heart Failure 2020; 13: 301-314. Among the student term project topics were, “Improving VAD Technology for the African American Community;” “Blood Pressure Measurement and Management in Black Ventricular Assist Device Users;” “A Multi-Factor Approach to Improve African American Heart Health;” “Innovative Design for Cystic Fibrosis in Women of Color.” Conclusions: Student response to the term project assignment was positive. Meetings with the students demonstrated the students’ interest in the topic. The ultimate success of this assignment will be achieved, if these students are sensitive to the special needs of U/U patients and incorporate these needs in their design of biomedical devices.

A43 SEX DIFFERENCES IN THE ASSOCIATION OF HIV WITH METABOLIC DYSFUNCTION-ASSOCIATED FATTY LIVER DISEASE (MAFLD)

Abstract Background People with HIV (PWH) are at high risk for metabolic dysfunction-associated fatty liver disease (MAFLD). In the general population, sex differences seem to exist in frequency and severity of MAFLD, with higher prevalence of MAFLD in men, but higher incidence of liver fibrosis in women. Less is known about sex differences in MAFLD and liver fibrosis in the setting of HIV infection. Purpose The aim of this study is to investigate the sex differences in the prevalence of MAFLD in PWH and the severity of liver fibrosis among this population. Method This was a multicenter cohort study including consecutive PWH who underwent screening for MAFLD and liver fibrosis by liver stiffness measurement (LSM) with associated controlled attenuation parameter (CAP). MAFLD was defined as the presence of hepatic steatosis, diagnosed as CAP&amp;gt;270 dB/m, plus any among type 2 diabetes, overweight (BMI&amp;gt;25 Kg/m2) or two other metabolic abnormalities. Significant liver fibrosis was diagnosed as LSM&amp;gt;8 kPa. Incidence of MAFLD and significant liver fibrosis was assessed through survival analysis. Result(s) 1359 PWH (25% females, 30% HCV coinfected) were included. Prevalence of MAFLD at baseline was lower in women than in men with HIV (17.7% vs. 24.3%, p=0.013). Conversely, there was no difference in prevalence of liver fibrosis (10.7% vs. 13.4%). Women with MAFLD were more frequently of black ethnicity (48% vs. 14%, p&amp;lt;0.001), had lower ALT (26.4+20.4 vs. 33.4+22.5; p=0.035), higher HDL cholesterol (1.46+0.57 vs. 1.11+0.33; p&amp;lt;0.001), lower triglycerides (1.69+0.96 vs. 2.47+2.63; p=0.035) compared to men with MAFLD. 485 of these PWH were followed for a median of 3.5 years. Incidence of MAFLD was similar between women and men with HIV. However, incidence of liver fibrosis was higher in women compared to men with HIV (7.0 per 100 person-years [PY] vs. 5.9 per 100 PY; p=0.035) (Figure 1). The higher incidence of significant liver fibrosis occurred particularly after the age of 50 years. On multivariable Cox regression analysis and after adjusting for age, presence of MAFLD (adjusted hazard ratio [aHR] 3.3, 95% CI 2.0-5.6) and female sex (aHR 2.2, 95% CI 1.3-3.5) were independent predictors of developing significant liver fibrosis while CD4 cell count was protective (aHR 0.99, 95% CI 0.99-0.99). Image Conclusion(s) MAFLD seems a sexual dimorphic disease in PWH. Despite having lower rates of MAFLD, women with HIV have higher incidence of significant liver fibrosis compared to men, especially after 50 years of age. Future studies should target adequate consideration of sex differences in clinical investigation of MAFLD to fill current gaps and implement precision medicine for PWH. Please acknowledge all funding agencies by checking the applicable boxes below None Disclosure of Interest None Declared

Performance of Non-invasive Biomarkers of Liver Fibrosis Amongst Hispanics and African Americans.

Liver biopsy is the gold standard for fibrosis staging. However, it is limited by significant complications. Non-invasive markers of fibrosis have been developed as an alternative to liver biopsy. The performance of these different markers varies with the etiology of liver fibrosis and possibly amongst different ethnicities. We aim to assess the performance of non-invasive markers of liver fibrosis amongst Hispanics and African Americans. This is a retrospective cohort analysis of patients who had liver biopsy as part of their evaluation of chronic liver disease. One hundred and twenty-six records were analyzed. Univariate and multivariate analyses were performed. Probit regression receiver operating characteristic curve analysis was used to assess the sensitivity of the different non-invasive biomarkers and underlying variables with respect to liver biopsy. The following non-invasive markers for fibrosis were used: Fibrosis-4 (FIB-4), aspartate aminotransferase (AST) to platelet ratio index (APRI), age-platelet, AST/alanine aminotransferase (AST/ALT) ratio, fibrosis cirrhosis index (FCI), and fibrosis index (FI). About two-thirds of the study population were African Americans with majority of the study population having chronic liver disease from viral infection. Minimal to no fibrosis by the METAVIR (an acronym for Meta-analysis of Histological Data in Viral Hepatitis) score was found in 58% of patients compared to 42% with moderate to severe fibrosis. Hispanics were more likely than Blacks to have hepatic steatosis. Age significantly increased the sensitivity and specificity of APRI and age-platelet scores. The AST/ALT score had a lower sensitivity for liver fibrosis in women compared to men in our study population. The sensitivity of FIB-4 and age-platelet was higher in Hispanics compared to African Americans while the opposite was the case for APRI, AST/ALT, FCI, and FI. Non-invasive biomarkers are useful in detecting liver fibrosis. FIB-4 and age-platelet have a high sensitivity in Hispanics while African Americans have a high sensitivity for APRI, AST/ALT, FCI, and FI. It is worth noting that these non-invasive biomarkers had variable performances when ethnicity, age, and sex were considered in our population.

Неалкогольная жировая болезнь печени и женское здоровье

This article is aimed to summarize data on the incidence and patterns of the non-alcoholic fatty liver disease (NAFLD) course among women of different age. The prevalence of NAFLD is growing worldwide. In general, the incidence of this liver disease in men is higher than in women. However, a detailed examination of various age groups revealed that in women of reproductive age, the NAFLD incidence was lower than in men; at the same time, after menopause, the disease incidence in women became equal to the incidence in men, even exceeded it according to some data. Ongoing epidemiological, clinical and experimental studies indicate a higher risk of NAFLD and liver fibrosis in women with postmenopause versus woman with premenopause, as well as that older women with NAFLD have a higher mortality rate than men. One of the key roles in metabolic changes that contribute, in particular, to the NAFLD development is assigned to estrogens. The relevance of the NAFLD detection and treatment in women is due to a significantly higher prevalence of age-adjusted cardiovascular diseases, 5-year mortality from all causes and 5-year cardiovascular mortality versus women without NAFLD. KEYWORDS: non-alcoholic fatty liver disease, fibrosis, steatosis, menopause, premenopause, pregnancy, estrogens, ursodeoxycholic acid. FOR CITATION: Livzan M.A., Syrovenko M.I., Krolevets T.S. Non-alcoholic fatty liver disease and women's health. Russian Medical Inquiry. 2023;7(5):310–317 (in Russ.). DOI: 10.32364/2587-6821-2023-7-5-9.

Sex-Related Signaling of Aldosterone/Mineralocorticoid Receptor Pathway in Calcific Aortic Stenosis

There are sex differences in the pathophysiology of aortic valve (AV) calcification in patients with aortic stenosis, although the molecular and cellular mechanisms have not been elucidated. Aldosterone (Aldo) promotes proteoglycan synthesis in valve interstitial cells (VICs) from mitral valves via the mineralocorticoid receptor (MR). We investigated the influence of sex in the role of Aldo/MR pathway in AV alterations in patients with aortic stenosis. MR was expressed by primary aortic VICs and in AVs from patients with aortic stenosis. MR expression positively correlated with VIC activation markers in AVs from both sexes. However, MR expression was positively associated with molecules involved in AV calcification only in AV from men. Aldo enhanced VIC activation markers in cells from men and women. Interestingly, Aldo increased the expression of calcification markers only in VICs isolated from men. In female VICs, Aldo enhanced fibrotic molecules. MR antagonism (spironolactone) blocked all the above effects. Cytokine arrays showed ICAM (intercellular adhesion molecule)-1 and osteopontin to be specifically increased by Aldo in male VICs. In AVs from men, MR expression positively associated with both ICAM-1 (intercellular adhesion molecule-1) and osteopontin. Only in female VICs, estradiol treatment blocked Aldo-induced VICs activation, inflammation, and fibrosis. These findings demonstrate that the Aldo/MR pathway could play a role in early stages of aortic stenosis by promoting VICs activation, fibrosis, and ulterior calcification. Importantly, Aldo/MR pathway is involved in fibrosis in women and in early AV calcification only in men. Accordingly, MR antagonism emerges as a new sex-specific pharmacological treatment to prevent AV alterations.

Analysis of the sensitivity and specificity of ultrasound elastometry of the liver in women with chronic hepatitis C

Introduction. Despite the success in the treatment of chronic hepatitis C (HCV), the incidence of HCV remains at a high level, and the assessment of the degree of liver fibrosis is relevant in all patients with HCV.The aim of the study was to conduct a comparative diagnosis of the stages of liver fibrosis in women with chronic hepatitis C according to ultrasound elastometry and biopsy.Materials and Methods. To achieve this goal, a comprehensive clinical, laboratory (including virological), instrumental examination of 93 patients with HCV of reproductive age was conducted.Results. When interpreting the results, it was found that ultrasound elastometry in women with chronic hepatitis C is comparable to the results of percutaneous puncture liver biopsy.Discussion. Chronic hepatitis causes significant economic damage to health systems. The main factor affecting the reduction of morbidity and the risk of complications is the early diagnosis of HCV infection and timely antiviral therapy. The main objective of therapy is to achieve a stable virological response (SVR), as well as to reduce the activity of inflammation and the stage of AF in patients with HCV. The isolated use of serum markers of fibrosis and ultrasound elastometry of the liver at the early stages of the disease is not informative enough, so it is advisable to use a combination of different techniques, and at the CP stage, a puncture biopsy can be safely replaced with ultrasound elastometry of the liver, especially for the purpose of dynamic monitoring of patients with HCV.Conclusion. According to the comparative ROC-analysis of the results of ultrasound elastography and puncture liver biopsy, the high sensitivity and specificity of these methods for diagnosing liver fibrosis was established. The comparability of ultrasound elastography of the liver with the results of puncture biopsy, in young women, increases with the progression of liver fibrosis, and can be used to determine its degree.

O-14 A SYNERGISTIC EFFECT OF PNPLA3 GENE POLYMORPHISM AND INSULIN RESISTANCE INCREASES THE RISK TO NON-ALCOHOLIC FATTY LIVER DISEASE IN PATIENTS WITH POLYCYSTIC OVARY SYNDROME

The patatin-like phospholipase 3 gene polymorphism (PNPLA3) has been consistently associated with non-alcoholic fatty liver disease (NAFLD) and its histological severity on different populations. In addition, increasing evidence demonstrates the association of NAFLD and polycystic ovary syndrome (PCOS), both associated with obesity, insulin resistance (IR) and metabolic syndrome (MS). Describe the prevalence of the PNPLA3 gene polymorphism and its impact on NAFLD susceptibility and progression in women with PCOS. This was a cross-sectional study enrolling 163 patients with PCOS. All the patients were evaluated for the presence of the PNPLA3 (rs738409 c.444C>G) polymorphism, hepatic steatosis at ultrasound and metabolic disorders. In patients with steatosis, transient hepatic elastography was performed to assess liver stiffness. In this population, evidence of hepatic steatosis was observed in 72.4% of them. The polymorphism was present in heterozygosis (CG) in 41.7% and in homozygosis (GG) in 8% of patients and was not statistically associated with the occurrence of NAFLD or clinically significant fibrosis (≥ F2). IR had a prevalence of 75% and, after evaluation by a multiple regression model, it was the main factor associated with the risk of NAFLD (B = 1.405, p = 0.026). A synergistic effect between IR and the presence of polymorphism on increasing the risk of NAFLD was observed (B = 2.047, p = 0.042). HDL values ≥ 49 mg/dL showed a negative association with NAFLD (B = - 1.578, p = 0.001). MS and IR, waist circumference, higher values of transaminases and lower levels of dehydroepiandrosterone sulfate were associated with clinically significant fibrosis. The PNPLA3 gene polymorphism did not present an independent association either with NAFLD or the development of clinically significant fibrosis in women with PCOS. However, the polymorphism interacts synergistically with IR and increases the risk of NAFLD.

ADSC Exosomes Mediate lncRNA-MIAT Alleviation of Endometrial Fibrosis by Regulating miR-150-5p.

BackgroundSecondary infertility remains a major complication of endometrial fibrosis in women. The use of exosomes from adipose-derived mesenchymal stem cells (ADSCs) has shown promising results for the treatment of endometrial fibrosis. However, the mechanisms of action of ADSC-exosome (ADSC-Exo) therapy remain unclear.Materials and MethodsAn endometrial fibrosis model was established in mice treated with alcohol and endometrial epithelial cells (ESCs) treated with TGF-β1. ADSCs were isolated from Sprague Dawley (SD) rats, and exosomes were isolated from ADSCs using ExoQuick reagent. Exosomes were identified by transmission electron microscopy (TEM), NanoSight, and Western blot analysis. The expression level of lncRNA-MIAT was detected by qPCR analysis. Western blot analysis was carried out to determine the protein levels of fibrosis markers (TGFβR1, α-SMA, and CK19). A dual-luciferase reporter gene assay was used to verify the relationship between target genes. The endometrial tissues of the endometrial fibrosis model were stained with HE and Masson’s trichrome.ResultsADSCs and ADSC-Exos were successfully isolated, and the expression level of lncRNA-MIAT was significantly down-regulated in endometrial tissue and the TGF-β1-induced ESC injury model, whereas ADSC-Exos increased the expression of lncRNA-MIAT in the TGF-β1-induced ESC model. Functionally, ADSC-Exo treatment repressed endometrial fibrosis in vivo and in vitro by decreasing the expression of hepatic fibrosis markers (α-SMA and TGFβR1) and increasing the expression of CK19. Moreover, miR-150-5p expression was repressed by lncRNA-MIAT in the TGF-β1-induced ESC injury model. The miR-150-5p mimic promoted TGF-β1-induced ESC fibrosis.ConclusionADSC-Exos mediate lncRNA-MIAT alleviation of endometrial fibrosis by regulating miR-150-5p, which suggests that lncRNA-MIAT from ADSC-Exos may be a viable treatment for endometrial fibrosis.

Comparative study of clinicopathological features, and risk factors of advanced fibrosis between genders with non-alcoholic fatty liver disease

Objective: To comparatively study the similarities and differences between the clinical, pathological, and risk factors of advanced fibrosis in men and women with non-alcoholic fatty liver disease (NAFLD). Methods: 267 patients with NAFLD diagnosed by liver biopsy were retrospectively included, and were divided into male and female groups. The difference of clinical and pathological indexes were compared between the two groups. The measurement data were in accordance with normal distribution. The comparison between the two groups was performed by independent sample t-test. The non-parametric test was used for non-normal distribution. The classification data were expressed as a percentage, and the chi-square test was used for comparison between groups. Logistic regression analysis was used to analyze the risk factors. Results: The age of onset of NAFLD was significantly lower in male than female patients (P < 0.01). There was no statistically significant difference between the male and female groups in terms of body mass index and the prevalence of type 2 diabetes (P > 0.05). Biochemical index: The levels of alanine aminotransferase, albumin, total bilirubin and uric acid were significantly higher in male than female patients (P < 0.01). Liver pathology: The proportion of ballooning degeneration was significantly lower in male than female patients (P < 0.01). There was not statistically significant difference between the two groups in the proportion of steatohepatitis score, non-alcoholic steatohepatitis (52.0% vs. 61.5%, P = 0.283) and advanced liver fibrosis (14.3% vs. 17.8%, P = 0.162). Thrombocytopenia was a common independent risk factor for advanced stage liver fibrosis (OR = 0.984, 0.978~0.989, P < 0.01). Type 2 diabetes was only an independent risk factor for advanced stage liver fibrosis in men (OR = 6.557, 1.667~25.782), P < 0.01). Elevated AST was only an independent risk factor for advanced stage liver fibrosis in women (OR = 1.016, 1.003~1.028, P = 0.012). Conclusion: In NAFLD patients, there are some clinical and pathological differences between genders. Platelets are a common predictor of advanced liver fibrosis in men and women. Type 2 diabetes in men and elevated aspartate aminotransferase in women can be regarded as independent risk factors for advanced liver fibrosis.

Plasma BCAA Changes in Patients With NAFLD Are Sex Dependent.

Plasma branched chain amino acid (BCAA) concentrations correlate positively with body mass index (BMI), measures of insulin resistance (IR), and severity of nonalcoholic fatty liver disease (NAFLD). Moreover, plasma BCAA concentrations also differ between the sexes, which display different susceptibilities to cardio-metabolic diseases. Assess whether plasma BCAA concentrations associate with NAFLD severity independently of BMI, IR, and sex. Patients visiting the obesity clinic of the Antwerp University Hospital were consecutively recruited from 2006 to 2014. A cross-sectional study cohort of 112 obese patients (59 women and 53 men) was divided into 4 groups according to NAFLD severity. Groups were matched for sex, age, BMI, homeostatic model assessment of IR, and hemoglobin A1c. Fasting plasma BCAA concentrations were measured by tandem mass spectrometry using the aTRAQ™ method. In the study cohort, a modest positive correlation was observed between plasma BCAA concentrations and NAFLD severity, as well as a strong effect of sex on plasma BCAA levels. Subgroup analysis by sex revealed that while plasma BCAA concentrations increased with severity of NAFLD in women, they tended to decrease in men. Additionally, only women displayed significantly increased plasma BCAAs with increasing fibrosis. Plasma BCAA concentrations display sex-dimorphic changes with increasing severity of NAFLD, independently of BMI, IR, and age. Additionally, plasma BCAA are associated with significant fibrosis in women, but not in men. These results highlight the importance of a careful consideration of sex as a major confounding factor in cross-sectional studies of NAFLD.

The estrogen-regulated lncRNA H19/miR-216a-5p axis alters stromal cell invasion and migration via ACTA2 in endometriosis.

Fibrotic tissue may contribute to the origin of some endometriosis-related symptoms, such as chronic pelvic pain and infertility. Alterations in the H19/miR-216a-5p/ACTA2 pathway may mediate the regulation of eutopic endometrial stromal cell (euESC) invasion and migration and may represent a potential mechanism underlying fibrous tissue formation or fibrosis in women with endometriosis. In this study, we aimed to determine the expression of H19 and ACTA2 in endometrial tissues of women with endometriosis. Two groups of 23 infertile women with endometriosis and 23 matched infertile women without endometriosis were investigated. Primary cultured cells of endometrial tissues were analyzed using RT-PCR and western blotting (WB) to determine expression of H19 and ACTA2. 5-Ethyl-2'-deoxyuridine, CCK8 and Transwell assays were used to study the functions of H19 and ACTA2. Human embryonic kidney 293 cells were used for luciferase assays to study miR-216a-5p binding sites with H19 and ACTA2. We found that H19 and ACTA2 levels were significantly higher in endometriosis euESCs than in control euESCs (P < 0.05) and were positively correlated in endometriosis euESCs. Luciferase assays indicated that H19 regulates ACTA2 expression via competition for inhibitory miR-216a-5p binding sites. Our results indicate that alterations in the estrogen/H19/miR-216a-5p/ACTA2 pathway regulated endometriosis euESC invasion and migration. Downregulation of H19 or ACTA2 inhibited endometriosis euESC invasion and migration; however, estrogen promoted endometriosis euESC invasion and migration via H19. The main limitation of our study was that experiments were conducted in vitro and further in vivo studies are required in the future. However, our study showed that primary cultured cells represented endometriosis cells more clearly than cell lines.

High Kynurenine:Tryptophan Ratio Is Associated With Liver Fibrosis in HIV-Monoinfected and HIV/Hepatitis C Virus-Coinfected Women.

BackgroundTryptophan catabolism, measured by the kynurenine:tryptophan (kyn/trp) ratio, is associated with gut microbiota alterations in people with HIV (PWH). We examined the association of the kyn/trp ratio with liver fibrosis in women with/without HIV infection.MethodsThe plasma kyn/trp ratio was measured in 137 HIV-monoinfected, HIV/hepatitis C virus (HCV)–coinfected, and uninfected women in the Women’s Interagency HIV Study. Fibrosis was estimated using FIB-4 in all participants and vibration-controlled transient elastography liver stiffness measurement (LSM) in a subset (n = 83). We used multivariable linear regression to evaluate the associations of infection status and kyn/trp ratio with relative differences in fibrosis estimates.ResultsThe median kyn/trp ratio (interquartile range) was 0.056 (0.045–0.066) in HIV/HCV-coinfected, 0.038 (0.032–0.046) in HIV-monoinfected, and 0.031 (0.025–0.034) in uninfected women (P < .001). After adjustment for sociodemographic, lifestyle, and metabolic factors, HIV monoinfection and HIV/HCV coinfection were associated with 37% (95% confidence interval [CI], 9% to 73%) and 164% (95% CI, 100% to 250%) greater FIB-4, respectively. When kyn/trp ratio was included, higher kyn/trp ratio was associated with greater FIB-4 (27% per kyn/trp doubling; 95% CI, 5% to 53%), and the associations of HIV monoinfection (29% per kyn/trp doubling; 95% CI, 2% to 63%) and HIV/HCV coinfection (123% per kyn/trp doubling; 95% CI, 63% to 203%) with greater FIB-4 were attenuated. Among those with LSM, higher kyn/trp ratio was associated with greater LSM (43% per kyn/trp doubling; 95% CI, 15% to 79%) in multivariable analysis.ConclusionsThe kyn/trp ratio is elevated in PWH and is associated with greater liver fibrosis. Tryptophan catabolism may modify the relationships between HIV, HCV, and fibrosis.

Abstract OT2-04-04: Multi-institution phase II trial of intraoperative electron beam radiotherapy boost at the time of breast conserving surgery with oncoplastic reconstruction in women with early-stage breast cancer

Abstract Background: In women amenable to breast conserving therapy, lumpectomy followed by adjuvant whole breast irradiation (WBI) remains the standard of care. Randomized trials demonstrate that addition of a lumpectomy cavity boost significantly reduces the risk of ipsilateral breast tumor recurrences but also increases the risk of breast fibrosis. Contemporary randomized trials define the lumpectomy cavity boost volume as a 1.7 cm isometric expansion on the lumpectomy cavity as delineated on CT. However, identifying the lumpectomy cavity can be challenging, especially in women that receive adjuvant chemotherapy and in cases in which surgical clips are not present. Recently, the use of oncoplastic techniques in breast conserving surgery has increased. These techniques are used to prevent the poor cosmetic results that can occur when a large volume of breast tissue is resected. Women that undergo oncoplastic reconstruction represent especially difficult cases for lumpectomy cavity delineation. Retrospective series have evaluated the use of intraoperative electron radiotherapy (IOERT) as a boost prior to WBI in women receiving lumpectomy without oncoplastic reconstruction. In the largest series of IOERT boost prior to WBI the local control rate of this approach was &amp;gt;99%. Prospective data regarding IOERT boost in women undergoing oncoplastic reconstruction are limited. The advantages of this approach include direct visualization/irradiation of the tumor bed, sparing the skin of irradiation, and reducing the treatment time by ˜1 week. We hypothesize that IOERT boost followed by WBI will result in acceptably low rates of grade 3 fibrosis in women undergoing lumpectomy with oncoplastic reconstruction. Trial Design: This is a single-arm, prospective study to evaluate the safety, toxicity and efficacy of IOERT boost at the time of breast conserving surgery in women with early-stage breast cancer undergoing oncoplastic reconstruction. Eligible women will receive 1 dose of 8 Gy to the surgical bed after lumpectomy but prior to oncoplastic reconstruction. Women will then receive adjuvant WBI of 40 Gy in 15 fractions or 50 Gy in 25 fractions. Eligibility: Key criteria include age≥18 yo, clinically node-negative stage I/II, any breast cancer subtype. Specific Aims: To determine the rate of grade 3 breast fibrosis at 1 year. Additional aims include surgical complication rates, cosmesis, and local regional cancer control. Statistical Methods: Safety will be evaluated by the rate of surgical complications necessitating hospital readmission or return to the operating room within 30 days of surgery+IOERT. If ≥4 events in the first 10 patients, ≥7 events in the first 20 patients, or ≥9 events in the first 30 patients are seen, the study will be halted. We hypothesize that the grade 3 fibrosis rate in our study will be ≤5%. Assuming an actual rate of 4%, an unacceptable rate of 9%, and a drop-out rate of 10%, the expected sample size is 176. Sites: Ohio State University, Avera Medical Group, University of North Carolina-Chapel Hill Patient Accrual: Current accrual is 5/176. Contact Information: Jose Bazan (jose.bazan2@osumc.edu) Funding Source: Intraop Medical Citation Format: Bazan JG, Stephens J, Agnese D, Skoracki R, Arneson K, Reiland J, Gupta G, Gallagher K, McElroy S, Gupta N, White JR. Multi-institution phase II trial of intraoperative electron beam radiotherapy boost at the time of breast conserving surgery with oncoplastic reconstruction in women with early-stage breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT2-04-04.

Association Between Inflammatory Markers and Myocardial Fibrosis.

Inflammation promotes adverse ventricular remodeling. T1 mapping has been used to noninvasively assess interstitial myocardial fibrosis. We examined the association of baseline markers of systemic inflammation with interstitial myocardial fibrosis measured by extracellular volume fraction (ECV) and native T1 mapping at 10-year follow-up in the MESA (Multi-Ethnic Study of Atherosclerosis). Seven hundred seventy-two participants had complete baseline data and underwent cardiac magnetic resonance imaging. All analyses were stratified by sex. Multivariable linear regression models were constructed to assess the associations of baseline CRP (C-reactive protein), IL (interleukin)-6, and fibrinogen with native T1 time and ECV. Longer native T1 times and higher percentages of ECV represent increasing myocardial fibrosis. A 1-SD increment of log-transformed IL-6 levels was associated with 0.4% higher ECV in men (β=0.4; P=0.05). CRP and fibrinogen were not associated to ECV. A 1-SD increment in the log-transformed CRP levels was associated with 4.9 ms higher native T1 (β=4.9; P=0.03). In women, the inflammatory markers did not demonstrate association with native T1 nor ECV. Higher IL-6 and CRP levels are associated with increased interstitial myocardial fibrosis assessed by cardiac magnetic resonance in men. However, no inflammatory markers were associated to myocardial fibrosis in women.

Abstract OT2-03-01: Multi-institution phase II trial of intraoperative electron beam radiotherapy boost at the time of breast conserving surgery with oncoplastic reconstruction in women with early-Stage breast cancer

Abstract Background: In women amenable to breast conserving therapy, lumpectomy followed by adjuvant whole breast irradiation (WBI) remains the standard of care. Randomized trials have demonstrated that the addition of a lumpectomy cavity boost significantly reduces the risk of ipsilateral breast tumor recurrences but also increases the risk of breast fibrosis. Contemporary randomized trials define the lumpectomy cavity boost volume as a 1.7 cm isometric expansion on the lumpectomy cavity as delineated on CT. However, identifying the lumpectomy cavity can be challenging, especially in women that receive adjuvant chemotherapy and in cases in which surgical clips are not present. Recently, the use of oncoplastic techniques in breast conserving surgery has increased. These techniques are used to prevent the poor cosmetic results that can occur when a large volume of breast tissue is resected. Women that undergo oncoplastic reconstruction represent especially difficult cases for lumpectomy cavity delineation. Retrospective series have evaluated the use of intraoperative electron radiotherapy (IOERT) as a boost prior to WBI in women receiving lumpectomy without oncoplastic reconstruction. In the largest series of IOERT boost prior to WBI the local control rate of this approach was &amp;gt;99%. Prospective data regarding IOERT boost in women undergoing oncoplastic reconstruction are limited. Advantages of this approach include direct visualization/irradiation of the tumor bed, sparing the skin of irradiation, and reducing the treatment time by ˜1 week. We hypothesize that IOERT boost followed by WBI will result in acceptably low rates of grade 3 fibrosis in women undergoing lumpectomy with oncoplastic reconstruction. Trial Design: This is a single-arm, prospective study to evaluate the safety, toxicity and efficacy of IOERT boost at the time of breast conserving surgery in women with early-stage breast cancer undergoing oncoplastic reconstruction. Eligible women will receive 1 dose of 8 Gy to the surgical bed after lumpectomy but prior to oncoplastic reconstruction. Women will then receive adjuvant WBI of 40 Gy in 15 fractions or 50 Gy in 25 fractions. Eligibility: Key inclusion criteria include age≥18 yo, clinically node-negative stage I/II, any breast cancer subtype. Specific Aims: Our primary aim is to determine the rate of grade 3 breast fibrosis at 1 year. Additional aims include surgical complication rates, cosmesis, and local regional cancer control. Statistical Methods: Safety will be evaluated by the rate of surgical complications necessitating hospital readmission or return to the operating room within 30 days of surgery+IOERT. If ≥4 events in the first 10 patients, ≥7 events in the first 20 patients, or ≥9 events in the first 30 patients are seen, the study will be halted. We hypothesize that the grade 3 fibrosis rate in our study will be ≤5%. Assuming an actual rate of 4%, an unacceptable rate of 9%, and a drop-out rate of 10%, the expected sample size is 176. Patient Accrual: Current accrual is 0 of 176. Contact Information: Soyhum McElroy (soyhun.mcelroy@osumc.edu) or Jose Bazan (jose.bazan2@osumc.edu) Funding Source: Intraop Medical Citation Format: Bazan JG, Stephens J, Terando A, Skoracki R, McElroy S, Sexton J, Gupta N, White J. Multi-institution phase II trial of intraoperative electron beam radiotherapy boost at the time of breast conserving surgery with oncoplastic reconstruction in women with early-Stage breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT2-03-01.

Coronary microvascular function and myocardial fibrosis in women with angina pectoris and no obstructive coronary artery disease: the iPOWER study

BackgroundEven in absence of obstructive coronary artery disease women with angina pectoris have a poor prognosis possibly due to coronary microvascular disease. Coronary microvascular disease can be assessed by transthoracic Doppler echocardiography measuring coronary flow velocity reserve (CFVR) and by positron emission tomography measuring myocardial blood flow reserve (MBFR). Diffuse myocardial fibrosis can be assessed by cardiovascular magnetic resonance (CMR) T1 mapping. We hypothesized that coronary microvascular disease is associated with diffuse myocardial fibrosis.MethodsWomen with angina, a clinically indicated coronary angiogram with <50 % stenosis and no diabetes were included. CFVR was measured using dipyridamole (0.84 mg/kg) and MBFR using adenosine (0.84 mg/kg). Focal fibrosis was assessed by 1.5 T CMR late gadolinium enhancement (0.1 mmol/kg) and diffuse myocardial fibrosis by T1 mapping using a modified Look-Locker pulse sequence measuring T1 and extracellular volume fraction (ECV).ResultsCFVR and CMR were performed in 64 women, mean (SD) age 62.5 (8.3) years. MBFR was performed in a subgroup of 54 (84 %) of these women. Mean native T1 was 1023 (86) and ECV (%) was 33.7 (3.5); none had focal fibrosis. Median (IQR) CFVR was 2.3 (1.9; 2.7), 23 (36 %) had CFVR < 2 indicating coronary microvascular disease, and median MBFR was 2.7 (2.2; 3.0) and 19 (35 %) had a MBFR value below 2.5. No significant correlations were found between CFVR and ECV or native T1 (R2 = 0.02; p = 0.27 and R2 = 0.004; p = 0.61, respectively). There were also no correlations between MBFR and ECV or native T1 (R2 = 0.1; p = 0.13 and R2 = 0.004, p = 0.64, respectively). CFVR and MBFR were correlated to hypertension and heart rate.ConclusionIn women with angina and no obstructive coronary artery disease we found no association between measures of coronary microvascular disease and myocardial fibrosis, suggesting that myocardial ischemia induced by coronary microvascular disease does not elicit myocardial fibrosis in this population. The examined parameters seem to provide independent information about myocardial and coronary disease.

Prevalence of nonalcoholic fatty liver disease and its metabolic risk factors in women of different ages and body mass index.

This study aims to investigate the prevalence of nonalcoholic fatty liver disease (NAFLD), to determine the metabolic risk factors of this disease, and to predict nonalcoholic steatohepatitis (NASH) with liver fibrosis in women of different ages and body mass index (BMI). In 2010-2011, a cross-sectional survey was conducted among 9,360 women at the health checkup center of Zhongnan Hospital (Wuhan, China). The probability of NASH with liver fibrosis was predicted using BAAT (BMI, age, alanine aminotransferase, and triglycerides) score. The prevalence of NAFLD increased from 5.3% to 18.8% in women younger than 45 years versus women aged 45 to 55 years and rose to 27.8% in women older than 55 years. In obese women, the prevalence of NAFLD was 48.4%. Women older than 45 years and obese women with NAFLD had more unfavorable metabolic risk factors. Multiple regression analyses showed that increased BMI and low aspartate aminotransferase-to-alanine aminotransferase ratio were closely related to NAFLD in women of different ages, whereas increasing BMI, BAAT score, age, high triglycerides, alanine aminotransferase, and low aspartate aminotransferase-to-alanine aminotransferase ratio were all closely related to NAFLD in obese women. The prevalence of NASH with a BAAT index of 3 or higher was 13.2% and 14.9% in women older than 55 years and obese women with NAFLD, respectively. Obese and postmenopausal women have a high prevalence of NAFLD and severe metabolic disorders. The prevalence of NASH seems to be considerably higher in obese and postmenopausal women with NAFLD.

Association of IL28B Polymorphism with Fibrosis, Liver Inflammation, Gender Respective Natural History of Hepatitis C Virus in Egyptian Patients with Genotype 4

The polymorphism of interleukin 28B (IL28B) rs12979860 is associated with spontaneous and treatment-induced clearance in hepatitis C virus (HCV) genotype 4 (G4). However, there is no information on its interaction with gender, moreover its association with intrahepatic inflammation in North Africans is not studied and its association with fibrosis in North Africans (especially Egyptians) is controversial. This study aims to explore the association between the minor allele of the IL28B rs12979860 polymorphism with gender, fibrosis and necroinflammation in Egyptian G4 HCV patients. IL28B rs12979860 was genotyped in 224 individuals, including 100 healthy controls and 124 consecutive patients with chronic HCV. Results showed (1) IL28B rs12979860 minor alleles associated with susceptibity to chronic HCV mainly in men not women, (2) no association between IL28B rs12979860 with fibrosis and necroinflammation activity, (3) the IL28B rs12979860 TT genotype associated with severe fibrosis in women only and with the necroinflammation activity in men using a recessive model. In conclusion, the IL28B rs12979860 polymorphism is not associated with fibrosis and liver inflammation in Egyptian HCV G4. Nonetheless, the TT genotype of IL28B rs12979860 polymorphism affects the natural history of each gender independently.