Upper Limit Of Normal Research Articles

Metabolic dysfunction-associated steatotic liver disease: The question of long-term high-normal alanine aminotransferase as a screening test

The growing prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is being driven by the obesity epidemic. The quest for solutions continues particularly with regard to early detection. This editorial comments on the utility of long-term high-normal alanine aminotransferase (ALT) in screening for MASLD. Chen et al found that new onset MASLD can be detected by repetitively high normal ALT. Implicit in this concept is the question of what should be the accepted upper limit of normal (ULN) for ALT. It was previously set at 40 IU/L based on studies that included people with subclinical liver disease but the new consensus is 30/19 U/L in healthy males/females. Thus, when Chen et al defines the ULN as 40 U/L, others may view it as excessively high. It is important to recognize the variables affecting ULN e.g. instrumentation, diurnal variations, exercise and ageing. These variables matter when the distinctions are subtle e.g. normal vs high-normal. In this regard, the utility of long-term high normal ALT as a disease marker could be enhanced by combining it with other biomarkers, imaging and MASLD genetics to create machine learning classifiers. All in all, Chen et al ’s work on long-term high normal ALT as a marker of new-onset MASLD deserves merit.

High-sensitive cardiac troponin T in patients with idiopathic inflammatory myopathies

Abstract Introduction Patients with idiopathic inflammatory myopathies (IIM) may have positive blood tests of cardiac troponin in absence of clinically detected cardiac disease. This situation is more common using high-sensitive cardiac troponin T (hs-cTnT) but there is limited information of the expected results according to type of IIM and prognostic value of this test in this group of patients. Methods Prospective study with 32 healthy controls and 61 patients with IIM without known cardiac condition. These patients with IIM were followed for 25 months. High-sensitive cardiac troponin T (Roche Elecsys hs-cTnT) was measured at baseline in both groups and a value of 14 pg/ml was the percentile 99th and considered the upper limit of normality (ULN). Results The median value of hs-cTnT was higher in patients with myopathies [12.0 (5.0; 35.0) vs. 5.0 (4.0; 6.2) P< 0.001] and the frequency of abnormal values were also more common in patients with IIM compared to controls (45.9% vs 6.2%, p<0.001). The frequency varied according to the type of myositis: Inclusion Body Myosytis (75%), Polymyositis (66.7%) , Dermatomyositis (42.1%) and Antisynthetase syndrome (38.5%). In terms of magnitude, 57% had mild elevations (1 to 3 x ULN) while 11% had levels 3 to 5 times ULN and 32% had troponin values > 5x ULN (Figure 1). Among patients with IIM, elevated levels of hs-cTnT were not associated with left ventricle global longitudinal strain < 18% or lower ejection fraction and was not associated with cardiovascular events during 25 months of follow-up (Figure 2). Conclusion Abnormal values of high-sensitive cardiac troponin T are common in patients with idiopathic inflammatory myopathies including levels similar to myocardial infaction. This elevation was not associated with echocardiographic abnormalities or cardiovascular events in patients with IIM.Figure 1Figure 2

Mechanisms leading to peri-procedural myocardial infarction in patients with focal versus diffuse coronary artery disease

Abstract Background PMI are characterized by an elevation in cardiac biomarkers, such as troponin, following PCI. Adherence to the 4th UDMIof PMI necessitates not only elevated cardiac biomarkers but also the presence of ECG changes, new loss of viable myocardium, or angiographic findings indicative of a procedural complication. Understanding the mechanisms underlying PMI and their associated factors is of paramount clinical significance. Our goal was to investigate the specific pathways contributing to the occurrence of PMI in stable patients undergoing PCI. Methods This prospective study was performed at 23 sites and enrolled patients with at least one epicardial lesion with an FFR≤0.80 planned to be treated by PCI. Each patient underwent a standardized physiological protocol, including manual FFR pullbacks with PPG calculation for the characterization of CAD patterns. The median PPG value (0.62) was used to divide patients into predominantly focal or diffuse disease. Troponin levels were measured after PCI, and patients exhibiting an elevation exceeding 5 times the upper limit of normal (ULN) were subject to evaluation by an independent clinical events committee. In addition, patients with large troponin elevation (>70 times above the ULN) were adjudicated as PMI as a standalone criterion. The primary objective was to investigate the mechanism leading to PMI in patients with focal versus diffuse CAD. Results Overall, 855 patients were included in this analysis, with 34.5% (295 patients) exhibiting a troponin elevation exceeding 5 times the ULN. Among these cases, 66 (7.7%) were adjudicated as PMI. The prevalence of secondary criteria for PMI was as follows: ECG changes at 7.6% (5/66), new loss of viable myocardium at 0%, side branch occlusion at 18.2% (12/66), and large troponin elevation at 84.8% (56/66). Diffuse disease (PPG < 0.62) was significantly associated with PMI (OR 1.71, 95% CI 1.03 to 2.88, p-value = 0.038). In the overall population, the occurrence of ECG changes after PCI was 0.7% in focal disease compared to 0.8% in diffuse disease (p-value=1.0). Side branch occlusion after PCI was observed in 0.7% in focal disease vs. 2.5% in diffuse disease (p-value=0.04), and large troponin elevation occurred in 4.8% in focal disease vs. 8.5% in diffuse disease (p-value=0.03). Additionally, PPG was significantly associated with the incidence of side branch occlusion (OR 1.71, 95% CI 1.03 to 2.88, p-value=0.038) and large troponin elevation after PCI (OR 1.83, 95% CI 1.06 to 3.22, p-value=0.038). Conclusion The presence of diffuse atherosclerosis, as defined by PPG, was linked to an increased risk of PMI. The mechanisms leading to PMI differed between patients with focal and diffuse disease. Patients with diffuse disease demonstrated a higher incidence of branch occlusion and large troponin elevation following PCI compared to those with focal CAD. Targeting patients with high PPG may improve outcomes after PCI.MACE by PPG

False-positive cardiac troponin I values in healthy athletes post COVID-19 Infection: concerning insights from a prospective cohort study

Abstract Background Cardiac troponin I and T (cTnI, cTnT) are cardiac-specific biomarkers that detect and quantify cardiomyocyte injury. In patients with symptoms possibly indicating acute myocardial infarction (AMI), detection of elevated cTnT or cTnI concentrations usually mandates invasive coronary angiography. Accordingly, false-positive cTnT or cTnI concentrations could have detrimental consequences. Unfortunately, little is known about the prevalence and triggers of false-positive cTnI concentrations. Based on two index cases seen by one of us, we hypothesized that false-positive cTnI values may be common after COVID-19 infection and that macrotroponin, a complex formed between endogenous cTn autoantibodies and circulating cTn, may be the underlying cause. Purpose We aimed to test these hypotheses in a prospective cohort study. Methods We prospectively investigated professional athletes coming to the mandatory return to sports investigation at least 10 days after COVID-19 infection between 2022 and 2023 in an observational study. The presence of false-positive cTnI was centrally adjudicated in individuals that had elevated cTnI concentrations with one (or two) high-sensitivity cTnI assays, but normal high-sensitivity cardiac troponin T concentrations and normal electrocardiography (ECG), normal echocardiography, and normal cardiac magnetic resonance imaging (CMR). Divergences in hs-cTn concentrations were investigated using sex-specific upper limits of normal (ULN) of 4 different assays (hs-cTnI: Alinity/Abbott Diagnostic, hs-cTnI: Atellica/Siemens Healthineers, hs-cTnI: Access Beckman Coulter; hs-cTnT: Cobas/Roche Diagnostics). Athletes were instructed to cease training 48 hours before blood testing. Athletes with divergent hs-cTn assay results underwent further analysis for macrotroponin using sucrose gradient ultracentrifugation. Results Among 35 enrolled athletes (median age 24 years, 19 women and 16 men), 18 athletes had normal hs-cTn concentrations with all four hs-cTnT/I assays. In 17 athletes (48.6%), hs-cTn concentration was increased in at least one assay above the ULN, mostly one hs-cTnI method (hs-cTnI, Alinity) with normal concentrations of the other assays and normal cardiac imaging results. In contrast, two athletes had elevations in all hs-cTnI/T assays. Sucrose gradient ultracentrifugation provided evidence of macrotroponin in 15 of the 17 athletes (88%). Conclusions False-positive cTnI values are common after COVID-19 infection and should be considered in the differential diagnosis. Assay interference by macrotroponin seems to be the underlying mechanisms in most individuals. Documentation of normal hs-cTnT concentrations helps in the early detection of false-positive cTnI values.

Safety of single-dose bedaquiline combined with rifampicin for leprosy post-exposure prophylaxis: A Phase 2 randomized non-inferiority trial in the Comoros Islands.

To reduce leprosy risk in contacts of patients with leprosy by around 50%, the World Health Organization (WHO) recommends leprosy post-exposure prophylaxis (PEP) using single-dose rifampicin (SDR). Results from a cluster randomized trial in the Comoros and Madagascar suggest that PEP with a double dose of rifampicin led to a similar reduction in incident leprosy, prompting the need for stronger PEP. The objective of this Phase 2 trial was to assess safety of a bedaquiline-enhanced PEP regimen (intervention arm, bedaquiline 800 mg with rifampicin 600 mg, BE-PEP), relative to the WHO recommended PEP with rifampicin 600 mg alone (control arm, SDR-PEP). From July 2022 to January 2023, consenting participants were screened for eligibility, including a heart rate-corrected QT interval (QTc) <450 ms and liver enzyme tests (ALT/AST) below 3× the upper limit of normal (ULN), before they were individually randomized 1:1 in an open-label design. Recruitment was sequential, by age group. Pediatric dosages were weight adjusted. Follow-up was done at day 1 post-dose (including ECG) and day 14 (including ALT/AST), with repeat of ALT/AST on the last follow-up at day 30 in case of elevation on day 14. The primary outcome was non-inferiority of BE-PEP based on a <10 ms difference in QTc 24 h after treatment administration, both unadjusted and adjusted for baseline QTc. Of 408 screened participants, 313 were enrolled, starting with 187 adults, then 38 children aged 13 to 17 years, and finally 88 children aged 5 to 12 years, of whom 310 (99%) completed all visits. Across all ages, the mean QTc change on BE-PEP was from 393 ms to 396 ms, not significantly different from the change from 392 ms to 394 ms on SDR-PEP (difference between arms 1.8 ms, 95% CI -1.8, 5.3, p = 0.41). No individual's QTc increased by >50 ms or exceeded 450 ms after PEP administration. Per protocol, all children were analyzed together, with no significant difference in mean QTc increase for BE-PEP compared to SDR-PEP, although non-inferiority of BE-PEP in children was not demonstrated in unadjusted analysis, as the upper limit of the 95% CI of 10.4 ms exceeded the predefined margin of 10 ms. Adjusting for baseline QTc, the regression coefficient and 95% CI (3.3; -1.4, 8.0) met the 10 ms non-inferiority margin. No significant differences in ALT or AST levels were noted between the intervention and control arms, although a limitation of the study was false elevation of ALT/AST during adult recruitment due to a technical error. In both study arms, one serious adverse event was reported, both considered unlikely related to the study drugs. Dizziness, nausea, headache, and diarrhea among adults, and headaches in children, were nonsignificantly more frequently observed in the BE-PEP group. In this study, we observed that safety of single-dose bedaquiline 800 mg in combination with rifampicin is comparable to rifampicin alone, although non-inferiority of QTc changes was demonstrated in children only after adjusting for the baseline QTc measurements. A Phase 3 cluster randomized efficacy trial is currently ongoing in the Comoros. ClinicalTrials.gov NCT05406479.

Efficacy and safety of immunotherapy combined with chemotherapy in patients with ES-SCLC: A systematic review and network meta-analysis of RCTs and RWSs.

To evaluate the efficacy and safety of programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors in the treatment of extensive-stage small-cell lung cancer (ES-SCLC), we conducted a systematic review and meta-analysis that included randomized controlled trials (RCTs) and real-world studies (RWS). By scanning PubMed, Web of science, Embase, and other relevant clinical information public databases, nine RCTs and eight RWSs involving 5205 patients were included in the study. We directly compared the differences between chemotherapy and PD-1/PD-L1 inhibitors plus chemotherapy, and determined the optimal treatment strategy through network meta-analysis (NMA). Compared to chemotherapy, the addition of PD-1/PD-L1 inhibitors significantly improves the overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) in SCLC patients. Regarding safety, both RCTs and RWSs indicated no significant difference in grade 3-4 adverse events between chemotherapy and chemoimmunotherapy. NMA showed serplulimab plus chemotherapy (Serp_Chemo) appears to provide the best OS, PFS, and ORR benefit, while nivolumab plus chemotherapy shows higher toxicity than other regimens. In subgroup analysis, for elderly patients (age ≥65) and non-elderly (age <65) patients, the most promising quality regimens for achieving better OS extension are atezolizumab plus chemotherapy (Atez_Chemo) and Serp_Chemo, respectively. For patients with PD-L1 ≥ 1% and lactate dehydrogenase (LDH) > upper limit of normal (ULN), there is no apparent OS benefit from immune therapy. In ES-SCLC treatment, adding PD-1/PD-L1 inhibitors to standard chemotherapy improves OS, PFS, and ORR, with Serp_Chemo shows the most promise. Atez_Chemo and Serp_Chemo provided better survival for elderly and non-elderly patients, respectively.

Endomysial antibodies or anti-tissue transglutaminase type 2 IgA antibodies as a confirmatory test in children with celiac disease.

The no-biopsy approach to diagnose celiac disease (CD), introduced in the 2012 European Society for Gastroenterology and Hepatology and Nutrition guidelines, requires an anti-endomysial antibody (EMA) confirmatory serology test following a high-positive immunoglobulin A anti-tissue transglutaminase-2 (anti-TG2) antibody ≥10 times the upper limit of normal (ULN). The aim of this retrospective study is to compare EMA positivity and high-positive anti-TG2 in patients who had their confirmatory test within two month of their first high-positiveanti-TG2 test. Among 933 patients who had high-positive anti-TG2 serology more than 10 times the ULN in their first sample, all had both high-positive anti-TG2 and positive EMA, most of them with very high EMA titers (99.6%) in their confirmatory test. In conclusion, we suggest that a repeated anti-TG2 test can replace the EMA test as the confirmatory serology test for the confirmation of the diagnosis of CD in the no-biopsy approach.

Changes in bone density and microarchitecture in adolescents undergoing a first kidney transplantation: a prospective study

Purpose Mineral bone disorder associated with chronic kidney disease (CKD-MBD) frequently persists after kidney transplantation (KTx), being due to pre-existing CKD-MBD, immunosuppressive therapies, and post-KTx hypophosphatemia. This study aimed to evaluate bone biomarkers and microarchitecture using high resolution peripheral quantitative computed tomography (HR-pQCT) at the time of KTx and 6 months thereafter and to compare these results with those of matched healthy controls (HC).Methods This study presented the single-center subgroup of patients aged between 10 and 18 years included in the prospective “Bone Microarchitecture in the Transplant Patient” study (TRANSOS-NCT02729142). Patients undergoing a first KTx were matched (1:2) with HC from the “Vitamin D, Bones, Nutritional and Cardiovascular Status” cohort (VITADOS) on sex, pubertal stage, and age.ResultsAt a median (interquartile range, IQR) age of 15 [13; 16] years, 19 patients (6 girls, 7 pre-emptive KTx, 7 steroid-sparing immunosuppressive strategies) underwent a first KTx, with a median [IQR] parathyroid hormone level of 1.9 [1.4; 2.9] the upper limit of normal (ULN). Higher total and trabecular bone densities, along with superior trabecular microarchitecture, were observed at KTx compared to HC. Six months post-KTx, patients had significantly impaired trabecular parameters at the radius, while results were not significantly different at the weight-bearing tibia, neither cortical parameters at both sites. Six months post-KTx, 6 (32%) patients still present with metabolic acidosis, 10 (53%) persistent hyperparathyroidism (always < 2 ULN), and 5 (26%) elevated FGF23 levels; 11 (58%) received phosphate supplementation.Conclusions: Bone density and microarchitecture at the time of KTx were superior compared to HC, but radial trabecular bone microarchitecture impairment observed 6 months post-KTx may reflect subtle albeit present post-KTx CKD-MBD.What is Known?• Mineral bone disorder associated with chronic kidney disease (CKD-MBD) frequently persists after kidney transplantation (KTx) and is associated with morbidity. However, biochemical parameters and dual X-ray absorptiometry (DXA) are poor predictors of the underlying bone disease.What is new?• The present study on 19 adolescent KTx recipients with adequate CKD-MBD control at the time of KTx reveals no significant bone disease compared to matched healthy controls. Microarchitecture impairment observes 6 months post-KTx may reflect subtle, albeit present, post-KTx CKD-MBD.

Primary Bilateral Macronodular Adrenal Hyperplasia: A Case Series from a Tertiary Hospital

Introduction: Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare etiology of Cushing’s syndrome characterized by the presence of multiple adrenal macronodules and variable levels of cortisol excess. Its pathogenesis is complex, involving mechanisms such as aberrant hormone receptors, adrenal paracrine ACTH production, and genetic germline pathogenic variants. However, management is not well established. Methods: This was a retrospective, observational study. We evaluated patients with PBMAH at our tertiary center. We aimed to describe the clinical, hormonal, and radiological characteristics; treatment approaches; and outcomes. Results: Twenty patients were included in this study. Patients had a mean age at diagnosis of PBMAH of 56.1 ± 11.1 years, and 10 patients (50.0%) were females. Most cases were initially investigated for adrenal incidentalomas. Median 8:00 a.m. serum cortisol after 1 mg dexamethasone overnight suppression test was 223.5 (73.1–698.6) nmol/L (8.11 [2.65–25.3] µg/dL), late-night salivary cortisol was 1.48 (0.765–3.21) times the upper limit of normal (ULN), and 24 h-UFC was 1.61 (0.42–3.64) times the ULN. One patient presented with the co-secretion of cortisol and aldosterone. Mean total adrenal size was 98.5 ± 25.6 mm, and the largest nodule size was 32.1 ± 9.09 mm. In six (31.6%) patients, the largest nodule had an attenuation higher than 10 HU. Germline pathogenic variants in ARMC5 were found in four (50.0%) of the eight tested patients who underwent genetic testing. Treatment strategies varied, with unilateral adrenalectomy often successfully controlling hypercortisolism in five (83.3%) of 6 patients with modest excess cortisol secretion. For mild autonomous cortisol secretion, active surveillance of comorbidities and appropriate treatment were not associated with progression of cortisol secretion after a median follow-up of 34.0 (10.5–83.0) months. Conclusion: This study underscores the need for personalized management strategies and identifies areas for future research to optimize the care of patients with PBMAH.

6570 Treatment of Cushing’s With Levoketoconazole: A Case Series

Abstract Disclosure: N. Chamorro-Pareja: None. M. Haines: None. L.E. Dichtel: Consulting Fee; Self; Lumos Pharma. Research Investigator; Self; Recordati, NovoNordisk, Perspectum Ltd, Lumos Pharma, Pfizer, Inc.. Stock Owner; Self; Marea Therapeutics. Other; Self; Third Rock Ventures. B.M. Biller: Consulting Fee; Self; Xeris Pharmaceuticals, Recordati Rare Diseases, Sparrow, Lundbeck. Background: Endogenous Cushing’s syndrome (CS) is a rare condition of excess cortisol secretion; the most common cause is a pituitary corticotroph tumor (Cushing’s disease [CD]). Medical treatment for CD is primarily used to control hypercortisolism in patients with persistent or recurrent disease after transsphenoidal surgery (TSS). Levoketoconazole (LKCZ), a steroidogenesis inhibitor, was FDA approved in January 2022 for CS treatment. This reports 3 cases of patients who were treated with LKCZ for recurrent CS. Clinical Cases: Case 1: 44-year-old (yo) male (M) with a history of CD with urinary free cortisol (UFC) &amp;gt;26x upper limit of normal (ULN) who was treated preoperatively with ketoconazole (KCZ) 1000 mg/day with UFC improved to 6x ULN. KCZ was discontinued at TSS, and he achieved remission post-operatively. He was lost to follow-up and re-presented after several years with worsening hypertension, muscle weakness, edema, and anxiety with UFC 28x ULN and a recurrent pituitary lesion on MRI. He declined repeat TSS and underwent radiation therapy (RT) and medical treatment. LKCZ was initiated at 150 mg twice daily (BID) and increased to 300 mg BID. At LKCZ 300 mg BID, he had a low UFC and mild nausea but an adequate serum morning cortisol (10.4 ug/dL, ref:6-18.4 ug/dL); LKCZ was reduced to 150 mg BID with resolution of symptoms (sxs) and normal UFC. Case 2: 56 yo M with a history of CD (UFC &amp;gt;3x ULN) who underwent 2 TSSs and RT over 10 years prior with eventual remission, but later recurred. Sxs included brain fog and mood disturbances. He achieved control with pasireotide but discontinued due to abnormal liver function tests. He was then treated with KCZ 400 mg/day but remained hypercortisolemic (LNSC 1.1x ULN) and was interested in trying a new medication, so was switched to LKCZ 150 mg BID with significant improvement of sxs and normalization of LNSC. Case 3: 54 yo F with presumed cyclic CD (negative whole-body and octreotide scans) with UFC 1.7x ULN and LNSC 3x ULN. TSS was performed with negative pathology; she had persistent hypercortisolemia and sxs including insomnia, fatigue, and mood disturbances. She was intolerant to and/or uncontrolled on 4 medications, including KCZ at 1000 mg/day that was discontinued due to a rash. She was started on LKCZ 150 mg BID and achieved normal LNSC and UFC after about 1 month. The drug was discontinued due to the development of a rash similar to that with KCZ. Conclusion: LKCZ is a new option for the treatment of CS in patients whose disease persists after TSS. These 3 patients had improvement of sxs and normalization of cortisol levels while on LKCZ, although one patient discontinued LKCZ due to a rash that was previously experienced with KCZ. The other two patients are being carefully monitored for liver function test elevation, QTc abnormalities and adrenal insufficiency with no issues to date. To our knowledge, this is the first case series of CS patients treated clinically with LKCZ. Presentation: 6/1/2024

12275 Effect Of Osilodrostat On Cardiovascular And Metabolic Manifestations Of Hypercortisolism In Patients With Non-Pituitary Cushing’s Syndrome: Findings From A Retrospective Observational Study (LINC 7)

Abstract Disclosure: N. Scheyer: Other; Self; Recordati Rare Diseases. J. Bertherat: Consulting Fee; Self; Novartis, HRA Pharma, Recordati Rare Diseases. B. Decoudier: Consulting Fee; Self; Recordati Rare Diseases. H. Lasolle: Speaker; Self; Recordati Rare Diseases. H. Lefebvre: Speaker; Self; Recordati Rare Diseases. D. Drui: None. C. Vaillant: None. J. Morera: None. F. Castinetti: Consulting Fee; Self; HRA Pharma Rare Diseases, Recordati Rare Diseases. Grant Recipient; Self; HRA Pharma Rare Diseases, Recordati Rare Diseases. J. Cristante: Grant Recipient; Self; HRA Pharma, Pfizer, Inc.. N. Chevalier: None. S. Fodil-Cherif: None. A. Antonellini: Employee; Self; Recordati Rare Diseases. W. Agbotounou: Employee; Self; Recordati Rare Diseases. A. Mueller: Employee; Self; Recordati Rare Diseases. A. Tabarin: Consulting Fee; Self; H Lundbeck A/S, Crinetics Pharmaceuticals, HRA Pharma, Recordati Rare Diseases. Introduction: Endogenous Cushing’s syndrome (CS) is associated with increased cardiovascular morbidity and mortality because of hypercortisolism. Osilodrostat, a potent oral 11β-hydroxylase inhibitor, is approved for patients (pts) with endogenous CS (EMA) and Cushing’s disease (CD; for whom pituitary surgery is not an option or has not been curative; FDA). The long-term safety and efficacy of osilodrostat has been demonstrated in Phase II (LINC 2, NCT01331239) and Phase III (LINC 3, NCT02180217; LINC 4, NCT02697734) studies of CD pts. Here, we investigated the effect of osilodrostat on clinical manifestations of hypercortisolism in a real-world, retrospective, observational study conducted in a heterogeneous patient population with non-pituitary CS (LINC 7; NCT05633953). Methods: Adult pts with non-pituitary CS who initiated osilodrostat prior to EU approval under the French Autorisation Temporaire d’Utilisation scheme and/or, once approved, in routine clinical practice were followed up retrospectively for up to 36 months. The primary endpoint was proportion of pts with mean urinary free cortisol (mUFC) ≤upper limit of normal (ULN) at week (W) 12, based on the modified intention-to-treat (mITT) population (pts with any cortisol measurement at W12 or not collected because of safety reasons). Secondary endpoints included cardiovascular and metabolic parameters, recorded every 4 or 12W, depending on clinical practice. No formal statistical hypothesis testing was performed; all analyses are descriptive. Results: 103 pts were enrolled (mean [SD] age: 59.3 years [15.5]; female 61.2% [n=63]; adrenal adenoma [16.5%, n=17/103; mITT: 9.6%, n=5/52], adrenocortical carcinoma [18.4%, n=19/103; mITT: 11.5%, n=6/52], macronodular adrenal hyperplasia [13.6%, n=14/103; mITT: 17.3%, n=9/52], ectopic adrenocorticotropic hormone secretion [51.5%, n=53/103; mITT: 61.5%, n=32/52]). Median (min-max) osilodrostat exposure and dose at baseline was 164.0 days (1-1178) and 5.0 mg/day (1-60), respectively. Median (min-max) osilodrostat dose at W12 and W36 was 6.0 mg/day (0-60) and 10.0 mg/day (0-120), respectively. 23/52 pts (44.2%; 95% CI 30.5-58.7) had mUFC ≤ULN at W12. Mean (95% CI) changes in cardiovascular and metabolic-related parameters from baseline to W12 and W36, respectively, were: systolic blood pressure (−5.7 [−17.9, −6.6] mmHg, n=29 and −6.3 [−19.0, −6.5] mmHg, n=11); diastolic blood pressure (−4.7 [−10.6, −1.1] mmHg, n=29 and −8.2 [−20.7, −4.3] mmHg, n=11); weight (−2.3 [−4.2, −0.4] kg, n=27 and −3.6 [−9.6, −2.5] kg, n=12); body mass index (−0.8 [−1.5, −0.2] kg/m2, n=27 and −1.2 [−3.2, −0.8] kg/m2, n=12). No new safety signals were identified. Conclusions: Findings from this real-world setting show that osilodrostat provides cortisol control alongside improvements in clinical manifestations of hypercortisolism in non-pituitary CS pts, alleviating the disease burden. Presentation: 6/1/2024

7317 CAHtalyst Pediatric: Results From The Randomized, Double-Blind, Placebo-Controlled Period Of A Phase 3 Trial Of Crinecerfont, A Corticotropin-Releasing Factor Type 1 Receptor Antagonist, In Children And Adolescents With Classic Congenital Adrenal Hyperplasia

Abstract Disclosure: K. Sarafoglou: Consulting Fee; Self; Neurocrine Biosciences, Inc., Crinetics Pharmaceuticals, Eton Pharmaceuticals, Spruce Biosciences. Research Investigator; Self; Neurocrine Biosciences, Inc., Adrenas Therapeutics, Spruce Biosciences. M.S. Kim: Advisory Board Member; Self; Spruce Biosciences. Research Investigator; Self; Neurocrine Biosciences, Inc., Diurnal, Spruce Biosciences. M. Lodish: None. E.I. Felner: None. L. Martinerie: None. N.J. Nokoff: Advisory Board Member; Self; World Athletics. Consulting Fee; Self; Ionis Pharmaceuticals Inc., Neurocrine Biosciences, Inc. M. Clemente: Consulting Fee; Self; AstraZeneca, Boehringer Ingelheim, Eli Lilly &amp; Company, Novo Nordisk. Research Investigator; Self; Eli Lilly &amp; Company, Novo Nordisk. P.Y. Fechner: Consulting Fee; Self; Neurocrine Biosciences, Inc., Eton Pharmaceuticals. Research Investigator; Self; Neurocrine Biosciences, Inc., Diurnal, Spruce Biosciences. M.G. Vogiatzi: Consulting Fee; Self; Adrenas Therapeutics, Eton Pharmaceuticals. Research Investigator; Self; Neurocrine Biosciences, Inc., Spruce Biosciences. P.W. Speiser: Advisory Board Member; Self; Adrenas Therapeutics, Chan Zuckerberg's Rare as One Initiative. Consulting Fee; Self; Roche Diagnostics. Research Investigator; Self; Neurocrine Biosciences, Inc.. Speaker; Self; Medscape, Wolters Kluter Publishing. J. Sturgeon: Employee; Self; Neurocrine Biosciences, Inc. E. Roberts: Employee; Self; Neurocrine Biosciences, Inc. G.S. Jeha: Employee; Self; Neurocrine Biosciences, Inc. J.L. Chan: Employee; Self; Neurocrine Biosciences, Inc. R. Farber: Employee; Self; Neurocrine Biosciences, Inc.. Introduction: Classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD), a genetic disorder characterized by cortisol deficiency and excess adrenal androgens, typically requires management with supraphysiological glucocorticoid (GC) doses. Crinecerfont is a novel oral CRF1 antagonist that reduced elevated ACTH and adrenal androgens in patients with 21OHD in 14-day, open-label Phase 2 studies. This Phase 3 study (CAHtalyst Pediatric: NCT04806451) evaluated whether crinecerfont can reduce androstenedione (A4) levels and supraphysiological GC doses in pediatric patients with 21OHD. Methods: Children and adolescents (2-17 yrs) with classic 21OHD, stable GC regimens at doses &amp;gt;12 mg/m2/d in hydrocortisone equivalents (HCe), A4 &amp;gt;midpoint of reference range, and 17-hydroxyprogesterone (17-OHP) &amp;gt;2x upper limit of normal (ULN) were randomized (2:1) to either crinecerfont (25, 50, or 100 mg BID based on weight) or placebo for 28 weeks. GC dosing was maintained stable for 4 weeks and then reduced, if possible, based on A4 levels to achieve a dose of 8-10 mg/m2/d while maintaining A4 control (≤120% of baseline or ≤ULN) by week 28. Results: In the 103 randomized participants (53 male; mean [range] age: 12 [4-17] yrs), demographics and baseline characteristics were similar between treatment arms (69 crinecerfont, 34 placebo). Mean baseline GC dose was 16.4 mg/m2/d HCe (92% on HC alone, 8% on a predniso[lo]ne-containing regimen). Baseline A4 (mean±SD) was 431±461 ng/dL and 17-OHP was 8682±6847 ng/dL. Over 95% completed the double-blind treatment period. At week 4 (end of GC-stable period), crinecerfont led to greater reductions in A4 vs placebo (least squares mean difference [LSMD]: -268 ng/dL; p=0.0002) (primary endpoint) and 17-OHP (LSMD: -6421 ng/dL; p&amp;lt;0.0001) (key secondary endpoint). At week 28, the crinecerfont arm had a greater percent reduction in GC dose while maintaining A4 control, vs placebo (LSMD: -24%; p&amp;lt;0.0001) (key secondary endpoint). Moreover, 30% of participants on crinecerfont achieved a protocol-defined physiological GC dose (≤11 mg/m2/d) while maintaining A4 control, vs 0% on placebo (nominal p=0.0009). The most common treatment-emergent adverse events (AEs) in the crinecerfont arm were headache (25% vs 6% for placebo), pyrexia (23% vs 24%), and vomiting (15% vs 30%). There were few serious AEs (5% overall) with none assessed as related to study drug. Conclusions: Crinecerfont, an oral CRF1 antagonist, represents a novel treatment option to improve androgen control in pediatric patients with classic 21OHD. In the largest interventional Phase 3 study conducted to date in these patients, crinecerfont led to a significant decrease in A4 while the GC dose was stable, enabling a significant percent reduction of supraphysiological GC doses while maintaining A4 control by 28 weeks. Crinecerfont was well tolerated overall. Presentation: 6/2/2024

7576 A Rare and Atypical Presentation of Bladder Paraganglioma in a Patient on Long-Term Left Ventricular Assist Device

Abstract Disclosure: S.D. Leungsuwan: None. S.J. Lee: None. S.D. Lim: None. L. Loh: None. Background: Paragangliomas (PGLs) are rare neuroendocrine tumors arising from chromaffin cells. Capable of producing catecholamines, functional PGLs often cause a myriad of autonomic symptoms and complications, including cardiomyopathy. We report a case of bladder PGL in a patient on Left Ventricular Assist Device (LVAD). Clinical Case: A 64-year-old Chinese Female with a history of non-ischaemic cardiomyopathy on long-term continuous LVAD and Cardiac Resynchronisation Therapy Defibrillator (CRT-D) was admitted for recurrent low LVAD flow &amp;lt;2 Litres per minute and labile mean arterial pressure (MAP) 57-151mmHg. She has been on long-term Nebivolol, Entresto, Hydralazine, and Sildenafil without recent dose adjustment. Workup for acute illnesses was non-contributory. 24-hour urine metanephrine and normetanephrine (NM) were 939nmol/d [normal 400-1500nmol/d] and 33883nmol/d [normal 600-1900nmol/d] respectively. Plasma free metanephrine and NM were 0.37nmol/L [normal &amp;lt;0.33nmol/L] and &amp;gt;10.00nmol/L [normal &amp;lt;0.99nmol/L] accordingly. A review of previous ultrasonography and Computed Tomography (CT) imaging revealed a right adnexal mass indenting the bladder which the patient formerly declined further assessment; adrenal glands were normal. FDG-PET CT was done and showed an isolated focus of increased tracer uptake corresponding with the right pelvic mass. An impression of likely bladder PGL was made. A multidisciplinary team including Cardiology, Anaesthesiology, Interventional Radiology (IR), Urology, Gynaecology, and Endocrinology was convened; the patient was recommended surgical resection of the tumor. Preoperatively, she was started on phenoxybenzamine 10mg BD and advised judicious fluid and salt intake. Nebivolol was continued while hydralazine was stopped. This achieved targets of i) MAP 70-80mmHg, ii) approximately 10mmHg MAP postural fluctuation, iii) sitting and standing heart rates 60-70 beats-per-minute (BPM) and 70-80BPM, and iv) no more than 1 PVC every 5 minutes. Two weeks later, she underwent IR-guided angioembolisation and tumor resection uneventfully. Intraoperatively, the patient had haemodynamic fluctuations requiring dynamic administrations of phentolamine, norepinephrine, epinephrine, vasopressin, glyceryl trinitrate, and sodium nitroprusside. Histopathology was consistent with PGL with intact SDH-A and SDH-B expression. Postoperatively, phenoxybenzamine was discontinued and no recurrent LVAD low flow was noted. Subsequent plans for repeat plasma metanephrines and genetic studies were made. Discussion: This case is the first to report an atypical presentation of PGL with LVAD low flow and labile blood pressure. The significant elevations of urine NM (17.8x upper normal limit) and plasma NM (&amp;gt;10.1x upper normal limit) also underline the concept of fold-elevations and post-test probability of PGL. Presentation: 6/3/2024

9330 Atumelnant (crn04894) Induces Rapid And Sustained Reductions In Serum And Urine Cortisol In Patients With Acth-Dependent Cushing Syndrome During A Phase 1b/2a, Single Center, 10-day, Inpatient, Open-Label Study

Abstract Disclosure: H. Elenius: Grant Recipient; Self; Crinetics Pharmaceuticals, Inc. R. McGlotten: Grant Recipient; Self; Crinetics Pharmaceuticals, Inc. C. Moore: Grant Recipient; Self; Crinetics Pharmaceuticals, Inc. Y.B. Omotosho: Grant Recipient; Self; Crinetics Pharmaceuticals, Inc. A. Ayala: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc. Y. Wu: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc. P.J. Trainer: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc. R.S. Struthers: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc. A. Krasner: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc. S.F. Betz: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc. L.K. Nieman: Grant Recipient; Self; Crinetics Pharmaceuticals, Inc.. Atumelnant is a potent, once-daily oral, nonpeptide, first-in-class competitive and selective melanocortin type 2 receptor (MC2R) antagonist that blocks ACTH-mediated G-protein activation and subsequent signaling. It is being developed for the treatment of ACTH-dependent Cushing Syndrome (ADCS) and classic congenital adrenal hyperplasia. We report preliminary data from the first-in-disease, dose-finding study of atumelnant in patients with ADCS (NCT05804669). Inpatient participants with active ADCS (24h urine free cortisol (UFC) &amp;gt;1.3xULN, ACTH &amp;gt;10 pg/mL) received atumelnant 80 mg once daily at 08.00 for 10 days (D1-10) followed by a 4-day washout. Endpoints included changes in UFC (upper limit of normal (ULN) 45 ug/d), early morning cortisol (EMC), and early morning ACTH (EMA, ULN 46 pg/mL). Daily questionnaires assessed adverse events (AEs) and signs and symptoms of adrenal insufficiency (AI) and ADCS. Data are shown as median (range). We report 5 participants (4 men; 4 Cushing disease, 1 ectopic ACTH; age 47 years (34-55)); each completed the study. All participants developed biochemical evidence of AI (EMC &amp;lt;5 mcg/dL) after 2 days (1-10) of atumelnant administration and then commenced physiologic hydrocortisone (HC) add-back. Compared to D1, biochemical disease control (normal UFC plus EMC &amp;lt;5 mcg/dL) was shown on D11 in all participants, while receiving HC replacement: UFC 252 mcg (99-293) vs 24 mcg (3.9-51); EMC 14 mcg/dL (10.7-18.1) vs 1.4 (1.0-4.7). This was associated with an increase in EMA: 52.1 pg/mL (33-1088) vs 78 pg/mL (48.8-4045). HC was discontinued when EMC was ≥7 mcg/dL, on D13 (D12-18). Many pre-existing features of ADCS improved during atumelnant administration, including poor concentration, insomnia (n=3 each); brain fog, anxiety, irritability (n=2 each); fatigue, poor memory, low libido, depression, edema and bloating (n=1 each). Low testosterone, neutrophilia (n=3 each) and leukocytosis (n=2) observed at baseline resolved during atumelnant administration. Anti-hypertensive therapy was paused or reduced in 3 subjects. New fatigue, headache, nausea, anorexia, edema (n=2 for each) all coincided with development of biochemical AI; most symptoms improved with HC add-back. Serious adverse events included AI and one non-treatment related transient GI bleed 19 days after the last dose. All other AEs were mild or moderate: transient increases of creatinine (n=2), and ALT (&amp;lt;3xULN, n=2). In conclusion, the first 5 patients with ADCS to receive once daily, oral atumelnant experienced rapid lowering of serum and urine cortisol and improvement or resolution of some signs and symptoms of ADCS. Atumelnant was generally well-tolerated. The observed compensatory increase in ACTH was not associated with loss of efficacy or clinical sequelae. This ongoing study will further explore the relationship between atumelnant dose, including lower doses, and therapeutic response. Presentation: 6/3/2024

Tissue transglutaminase immunoglobulin A exceeds endomysial antibody in specificity of celiac diagnosis at ≥10 times the upper limit of normal.

Serologic diagnosis using tissue transglutaminase immunoglobulin A (TTG-IgA) and endomysial antibody (EMA) is being integrated into the care of pediatric patients with positive screening for celiac disease. The purpose of this study was to assess the utility of EMA in pediatric patients being considered for serologic diagnosis. Patients with TTG-IgA testing performed between May 1, 2022 and April 30, 2023 and with subsequent duodenal biopsy within 6 months were included. TTG-IgA serum samples were frozen and sent for EMA testing and titer. EMA was evaluated for positivity and TTG-IgA (normal <15 u/mL) for elevation <10 times (10x) the upper limit of normal (ULN) and ≥10x ULN (≥150 u/mL). Sensitivity and specificity of EMA and TTG-IgA were calculated using biopsy histology as the gold standard. Four hundred and eighty-six patients were included. The sensitivity and specificity of TTG-IgA ≥15 u/mL was 87.5% and 95.4% while EMA was 77.5% and 97.3%. For patients with TTG-IgA ≥10x ULN the specificity was 99.3%. The positive predictive value of TTG-IgA at ≥10x ULN was 91.4% and for EMA was 83.6%. All three patients with false positive TTG-IgA ≥10x ULN also had false positive EMA, and two of these patients had type 1 diabetes mellitus. TTG-IgA has greater sensitivity at the screening threshold of ≥15 u/mL and greater specificity and positive predictive value at ≥10x ULN than EMA. TTG-IgA at ≥10x ULN is superior to EMA for the serologic diagnosis of celiac disease.

Identifying abnormal exertional breathlessness in COPD: comparing mMRC and CAT with CPET

Chronic obstructive pulmonary disease (COPD) management is guided by the respiratory symptom burden, assessed using the modified Medical Research Council (mMRC) scale and/or COPD Assessment Test (CAT). What is the ability of mMRC and CAT to detect abnormally high exertional breathlessness on incremental cardiopulmonary cycle exercise testing (CPET) in people with COPD? Analysis of people aged ≥40 years with post-bronchodilator FEV1/FVC<0.70 and ≥10 smoking pack-years from the Canadian Cohort Obstructive Lung Disease study. Abnormal exertional breathlessness was defined as a breathlessness (Borg 0-10) intensity rating > upper limit of normal (ULN) at the symptom-limited peak of CPET using normative reference equations. We included 318 people with COPD (40% women), age 66.5±9.3 years (mean±SD), FEV1 79.5±19.0%predicted; 26% had abnormally low exercise capacity (V'O2peak <lower limit of normal). Abnormally high exertional breathlessness was present in 24%, including 9% and 11% of people with mMRC=0 and CAT<10, respectively. A mMRC≥2 and CAT≥10 was most specific (95%) to detect abnormal exertional breathlessness, but had low sensitivity of only 12%. Accuracy for all scale cut-offs or combinations was <65%. Compared with 'true negatives', people with abnormal exertional breathlessness but low mMRC and/or CAT scores ('false negatives') had worse self-reported and physiological outcomes during CPET, were more likely to have physician-diagnosed COPD, but were not more likely to have any respiratory medication (37% versus 30%; mean difference 6.1%; 95% confidence interval -7.2 to 19.4; p=0.36). In COPD, mMRC and CAT have low concordance with CPET and fail to identify many people with abnormally high exertional breathlessness.

Vibration-controlled transient elastography for significant fibrosis in treatment-naïve chronic hepatitis B patients: A systematic review and meta-analysis.

Accurate diagnosis of significant liver fibrosis in patients with chronic hepatitis B (CHB) is crucial when determining whether to initiate antiviral treatment (AVT). We conduct a meta-analysis to assess the diagnostic performance of vibration-controlled transient elastography (VCTE) for significant liver fibrosis in AVT-naïve CHB patients with serum alanine transaminase (ALT) levels within 5-fold the upper limit of normal (ULN). The Ovid-Medline, EMBASE, Cochrane, and KoreaMed databases were searched to identify studies that compared the performance of VCTE and liver biopsy (reference standard) when diagnosing significant liver fibrosis (≥F2) in AVT-naïve CHB patients with ALT within 5-fold the ULN. A hierarchical summary receiver operating characteristic curve (HSROC) and bivariate model were performed to evaluate the diagnostic performance of VCTE in the meta-analysis. Eight studies (2,003 patients) were included. The summary sensitivity and specificity for diagnosis of significant liver fibrosis were 0.78 (95% confidence interval [CI], 0.66-0.86) and 0.72 (95% CI, 0.60-0.82), respectively. The HSROC for the diagnosis of significant liver fibrosis was 0.81 (95% CI, 0.72-0.86). The optimal cutoff value of VCTE for diagnosis of significant liver fibrosis was 7.7 kPa with a sensitivity of 0.64 (95% CI, 0.50-0.76) and specificity of 0.83 (95% CI, 0.72-0.90). Our study demonstrated that VCTE has an acceptable diagnostic performance for significant liver fibrosis in AVT-naïve CHB patients with ALT within 5-fold the ULN.

Liver-related aspects of valoctocogene roxaparvovec gene therapy for hemophilia A: expert guidance for clinical practice

AbstractAdeno-associated virus–based gene therapy (valoctocogene roxaparvovec) is an attractive treatment for hemophilia A. Careful clinical management is required to minimize the risk of hepatotoxicity, including assessment of baseline liver condition to determine treatment eligibility and monitoring liver function after gene therapy. This article describes recommendations (developed by a group of hemophilia experts) on hepatic function monitoring before and after gene therapy. To prevent harmful liver-related effects, gene therapy is contraindicated in patients with uncontrolled liver infections, autoimmune hepatitis, liver stiffness ≥8 kPa, or cirrhosis. Before using gene therapy in patients with liver steatosis or other liver disorders, the risk of liver damage should be considered using a highly individualized approach. Treatment is not recommended in patients with abnormal liver enzymes, including alanine aminotransferase (ALT) at any level above the upper limit of normal (ULN). Therefore, pretreatment assessment of liver health should include laboratory tests, abdominal ultrasound, and liver stiffness measurements by transient elastography (TE). In the first year after therapy, ALT levels should be monitored 1 to 2 times per week to detect elevations ≥1.5× ULN, which may require immunosuppressant therapy. Patients with ALT elevation should receive prednisone 60 mg/d for 2 weeks, followed by stepwise tapering when ALT returns to baseline. ALT monitoring should continue long term (every 3-6 months), along with abdominal ultrasound (every 6 months) and TE (yearly) evaluations. When patients with good liver health are selected for treatment and closely monitored thereafter, ALT elevations can be promptly treated and are expected to resolve without long-term hepatic sequelae.

Prevalence and etiotypes of persistent airflow obstruction in the general population across the lifetime

Background and objectivesDifferent factors (etiotypes) can lead to persistent airflow obstruction (PAO) across the lifetime, including genetic factors, abnormal lung development, cigarette smoking, traffic pollution exposure, respiratory infections and asthma. Here we explore the prevalence of PAO and associated etiotypes in the general population in different age bins. MethodsWe studied 664 individuals with PAO (FEV1/FVC post bronchodilation (post-BD) below the lower limit of normal (LLN)) and 11,522 with normal lung function (FEV1/FVC, FEV1 and FVC ≥ LLN and ≤ upper limit of normal (ULN) post-BD) included in the LEAD Study (NCT01727518), a general population cohort in Vienna (Austria). For analysis, participants were stratified in three age bins (<25, 25-<50 and ≥ 50 years of age). ResultsPAO occurred in 3.8 % in females and 5.6 % in males of the cohort, and it increased with age. Most participants with PAO (57.5 %) reported respiratory symptoms, indicating a high burden of disease. PAO was associated with male sex (25-<50 years), ever smoking (>50 years), increased number of pack years (25-<50 years, >50 years), not being breastfed (<25 years) and ever diagnosis of asthma (in all age bins). Etiotypes varied by age bins with cigarette smoking being the most prevalent one, often in combination with traffic pollution exposure. ConclusionIn the general population PAO occurs in about 5 % of participants with a higher prevalence in older individuals. Etiotypes and associated factors for PAO accumulate with age.

Factors associated with pre-treatment hyperferritinemia in patients with chronic hepatitis C virus infection

Pre-treatment host and viral factors may affect serum ferritin levels in patients with hepatitis C virus (HCV) infection. We delineated pre-treatment factors associated with hyperferritinemia in these patients. 1682 eligible patients underwent pre-treatment assessment for serum ferritin and various host/viral factors. Univariate and multivariate logistic regression analyses were conducted to evaluate factors associated with hyperferritinemia. Multivariate logistic regression analyses revealed that age > 50 years (adjusted odds ratio [OR]: 1.38 (95% confidence interval [CI] 1.09–1.74), p = 0.008), fibrosis stage ≥ F3 (adjusted OR: 1.36 (95% CI 1.04–1.77), p = 0.02), fibrosis index based on four parameters (FIB-4) > 3.25 (adjusted OR: 1.46 (95% CI 1.11–1.92), p = 0.01), presence of metabolic dysfunction-associated steatotic liver disease (MASLD) (adjusted OR: 1.43 (95% CI 1.21–1.76), p = 0.001), and alanine transaminase (ALT) > 2 folds upper limit of normal (ULN) (adjusted OR: 2.87 (95% CI 2.20–3.75), p < 0.001) were associated hyperferritinemia. The log10 value of HBV or HCV viral load was not associated with the log10 value of ferritin level (Spearman’s rank correlation coefficient: − 0.025, p = 0.81 and 0.002, p = 0.92). In conclusion, host factors, rather than viral factors, are associated with hyperferritinemia in patients with HCV.