Hereditary Hemochromatosis Patients Research Articles

Prevalence of C282Y, H63D and S65C gene mutations in patients with hyperferritinemia undergoing therapeutic phlebotomy suspected of having hereditary hemochromatosis

Background: Hemochromatosis is an autosomal recessive disorder caused by excessive iron overload in parenchymal organs. In Brazil, the prevalence of hereditary hemochromatosis (HH) may vary compared to other countries due to different ethnical backgrounds according to the geographic region studied. The prevalence of C282Y mutation of the HFE gene ranges from three to eight times lower in Brazilians than in Caucasians of Northern European origin. Methods: A retrospective cross-sectional study was carried out in 222 patients submitted to therapeutic phlebotomy between March 2011 and July 2014 in a tertiary hospital blood center. The prevalence of HH was determined in 89 (47.3%) out of 188 (84.6%) patients presenting hyperferritinemia, and divided in two genotype groups: C282Y mutation and other mutations. The HH patients’ geographical and clinical characteristics, serum ferritin rate (SF) and transferrin saturation (TS) were analyzed. Results: The HH group consisted of 71 males (79.7%) and 18 (20.3%) females, with a median age of 51.5 ± 10.6 years. There were 36 (40.0%) symptomatic patients and 65 (73.0%) tested positive for the HFE mutation. The initial baseline TS values were significantly higher in primary HH patients (48.6%, IC 95% 43.2% - 55.7%) compared to those with secondary HH (35.0%, IC 95% 27.5% 41.8%, p=0.001). Conclusion: The prevalence of C282Y mutation was higher in this population from the South region compared to previous reports in the Brazilian population, yet inferior to that of Northern Europeans.

Eicosanoids and Oxylipin Signature in Hereditary Hemochromatosis Patients Are Similar to Dysmetabolic Iron Overload Syndrome Patients but Are Impacted by Dietary Iron Absorption

Introduction: Oxylipins are mediators of oxidative stress. To characterize the underlying inflammatory processes and phenotype effect of iron metabolism disorders, we investigated the oxylipin profile in hereditary hemochromatosis (HH) and dysmetabolic iron overload syndrome (DIOS) patients. Methods: An LC-MS/MS-based method was performed to quantify plasma oxylipins in 20 HH and 20 DIOS patients in fasting conditions and 3 h after an iron-rich meal in HH patients. Results: Principal component analysis showed no separation between HH and DIOS, suggesting that the clinical phenotype has no direct impact on oxylipin metabolism. 20-HETE was higher in DIOS and correlated with hypertension (p = 0.03). Different oxylipin signatures were observed in HH before and after the iron-rich meal. Discriminant oxylipins include epoxy fatty acids derived from docosahexaenoic acid and arachidonic acid as well as 13-HODE and 9-HODE. Mediation analysis found no major contribution of dietary iron absorption for 16/22 oxylipins significantly affected by the meal. Discussion: The oxylipin profiles of HH and DIOS seemed similar except for 20-HETE, possibly reflecting different hypertension prevalence between the two groups. Oxylipins were significantly affected by the iron-rich meal, but the specific contribution of iron was not clear. Although iron may contribute to oxidative stress and inflammation in HH and DIOS, this does not seem to directly affect oxylipin metabolism.

The potential impact of hereditary hemochromatosis on the heart considering the disease stage and patient age-the role of echocardiography.

Hereditary hemochromatosis (HH) is a genetic disease that leads to increased iron accumulation in several organs. Cardiomyocytes are highly susceptible to this damage owing to their high iron uptake, and cardiovascular complications account for 1/3 of the deaths in the natural course of HH. Additionally, excess iron intake and associated oxidative stress may accelerate the aging of the cardiovascular system, regardless of the age of patients with HH. We aimed to investigate the role of standard and speckle-tracking echocardiography (STE) in revealing heart differences in patients with HH considering the disease stage and the patient age. Consecutive patients with HH (n = 58) without heart pathologies (except hypertension) and 29 age- and sex-matched healthy individuals underwent echocardiography. Patients were compared according to the time since HH diagnosis (the recently diagnosed HH group [31 patients] with diagnosed HH for less than 6 months and had no more than one venesection; the medium group [11 patients] with diagnosed HH between 6 and 24 months; and the long-lasting group [16 patients] with diagnosed HH for more than 2 years) and the quartile contribution of their age. Standard echocardiography revealed differences in diastolic parameters between patients with HH and controls, which were the most prominent between healthy and long-lasting HH patients. Regarding systolic function, left ventricular ejection fraction was lower in HH patients, with the most evident differences between the healthy and recently diagnosed HH patients. STE revealed additional differences in systolic parameters, with LV rotation the worst in recently diagnosed patients and its increase in patients with medium and long-lasting HH. Significantly worse peak systolic longitudinal strain values were observed in all patients with HH. Analyses of the results according to the age quartiles of patients with HH revealed that some changes ocurred earlier than expected according to age. Echocardiography can reveal possible heart damage in HH patients at different stages of the disease and highlight potential features of accelerated myocardial aging in these patients.

Analysis of Hand Joint Space Morphology in Women and Men with Hereditary Hemochromatosis

Hereditary hemochromatosis (HH) causes unbalanced iron deposition in many organs including the joints leading to severe cartilage loss and bone damage in the metacarpophalangeal joints (MCPJ). High-resolution peripheral quantitative computed tomography (HR-pQCT) and its joint space width (JSW) quantification algorithm quantifies in vivo 3D joint morphology. We therefore aimed to (i) determine feasibility and performance of the JSW algorithm in HH, (ii) quantify joint space morphology, and (iii) investigate the relationship between morphological and clinical parameters in HH. Here, we performed an exploratory study on 24 HH patients and sex- and age-matched controls using HR-pQCT imaging of MCPJ. Mineralized bone structure was automatically segmented from the grayscale image data and periosteal surface bone masks and joint space masks were generated. Mean, minimal, and maximal joint space width (JSW; JSW.MIN; JSW.MAX), JSW heterogeneity (JSW.SD), JSW asymmetry (JSW.AS), and joint space volume (JSV) were computed. Demographics and, for HH patients, disease-specific parameters were recorded. Segmentation of JS was very good with 79.7% of MCPJs successfully segmented at first attempt and 20.3% requiring semi-manual correction. HH men showed larger JSV at all MCPs (+ 25.4% < JSV < + 41.8%, p < 0.05), larger JSW.MAX at MCP 3-4 (+ 14%, 0.006 < p < 0.062), and wider JSW (+ 13%, p = 0.043) at MCP 4 relative to HH women. Compared to controls, both HH men and HH women showed larger JSW.AS and smaller JSW.MIN at all MCP levels, reaching significance for HH men at MCP 2 and 3 (JSW.AS: + 323% < JSW.AS < + 359%, 0.020 < p < 0.043; JSW.MIN: − 216% < JSW.MIN < − 225%, p < 0.043), and for women at MCP 3 (JSW.AS: + 180%, p = 0.025; JSW.MIN: − 41.8%, p = 0.022). Time since HH diagnosis was correlated positively with MCP 4 JSW.AS and JSW.SD (0.463 < ρ < 0.499, p < 0.040), and the number of phlebotomies since diagnosis was correlated with JSW.SD at all MCPs (0.432 < ρ < 0.535, p < 0.050). HR-pQCT-based JSW quantification in MCPJ of HH patients is feasible, performs well even in narrow JS, and allows to define the microstructural joint burden of HH.

Protein Susceptibility to Peroxidation by 4-Hydroxynonenal in Hereditary Hemochromatosis.

Iron overload caused by hereditary hemochromatosis (HH) increases free reactive oxygen species that, in turn, induce lipid peroxidation. Its 4-hydroxynonenal (HNE) by-product is a well-established marker of lipid peroxidation since it reacts with accessible proteins with deleterious consequences. Indeed, elevated levels of HNE are often detected in a wide variety of human diseases related to oxidative stress. Here, we evaluated HNE-modified proteins in the membrane of erythrocytes from HH patients and in organs of Hfe-/- male and female mice, a mouse model of HH. For this purpose, we used one- and two-dimensional gel electrophoresis, immunoblotting and MALDI-TOF/TOF analysis. We identified cytoskeletal membrane proteins and membrane receptors of erythrocytes bound to HNE exclusively in HH patients. Furthermore, kidney and brain of Hfe-/- mice contained more HNE-adducted protein than healthy controls. Our results identified main HNE-modified proteins suggesting that HH favours preferred protein targets for oxidation by HNE.

DENND3 p.L708V activating variant is involved in the pathogenesis of hereditary hemochromatosis via the RAB12/TFR2 signaling pathway.

Pathogenic variants in HFE and non-HFE genes have been identified in hereditary hemochromatosis (HH) in different patient populations, but there are still a considerable proportion of patients with unexplained primary iron overload. We recently identified in Chinese patients with unexplained primary iron overload a recurrent p.L708V variant in the differentially expressed in normal and neoplastic cells domain 3 (DENND3) gene, functioning as a guanine nucleotide exchange factor for small GTpase Rab12 which down-regulates TfR expression in mice. We aim to investigate the pathogenicity and the underlying mechanism of the DENND3 p.L708V variant in HH patients. Patients with primary iron overload were analyzed for DENND3 p.L708V. TFR2 and hepcidin expression in livers were examined in HH patients harboring DENND3 p.L708V. The effects of DENND3 p.L708V on RAB12/TFR2 and downstream iron metabolic pathways were investigated in vitro and in vivo. Six of 31 patients with HH (19.35%) harbored the DENND3 p.L708V variant. The expression of TFR2 and hepcidin was decreased in the liver of HH patients with DENND3 p.L708V. Cells transfected with the DENND3 p.L708V vector showed up-regulation of RAB12 expression and TFR2 degradation in lysosomes, and down-regulation of the pSMAD1/5 and hepcidin. Mice models infected with adeno-associated virus expressing DENND3 p.L708V variant showed higher total serum iron concentrations and decreased HAMP level, increased amount of iron accumulation and the down-regulated of TFR2 expression in the liver. The DENND3 p.L708V activating variant down-regulates hepcidin expression through the DENND3/RAB12/TFR2 axis, which may represent a potential novel pathogenic factor of HH.

Rusfertide Analog-PN23114 As a Hepcidin Mimetic Provides Efficacy Benefits in Conjunction with Phlebotomy in Mouse Model for Hereditary Hemochromatosis

Hepcidin deficiency in hereditary hemochromatosis (HH) leads to hyperabsorption of dietary iron and primary iron overload (Nemeth E., Science 2004). Therapeutic phlebotomy is used to reduce organ iron-overload in HH patients. However, persistent high transferrin-saturation (TSAT%) may result in toxic labile iron that can deposit in organs, leading to tissue damage and subsequent organ dysfunction. Additionally, newly diagnosed patients with severe iron overload require frequent phlebotomies during the induction phase of therapy that can last for many months, during which TSAT% levels may continue to be high even when serum ferritin levels are reduced. Rusfertide is a hepcidin mimetic peptide that has demonstrated potential benefit in reducing the need for therapeutic maintenance phlebotomy in a Phase 2 trial with hemochromatosis subjects who have previously required chronic phlebotomies to reduce and maintain ferritin and liver iron values within normal range (Kowdley KV, AASLD Hepatology 2021). To evaluate the potential benefits of co-treatment of hepcidin mimetic during induction phase of clinical management, we evaluated additive effects of PN23114 in combination with phlebotomy in HJV-/- mouse model for HH (129S-Hjvtm1Nca/J; Andrews NC, J Clin Invest. 2005). PN23114 is an analog of rusfertide with a single amino acid change and with similar pharmacokinetic and pharmacodynamic characteristics. Male HJV-/- mice at 8-12 weeks of age were treated with either PN23114 (7.5 mg/kg, TIW), phlebotomy (~0.3mL blood drawn, QW), or combination of both for a total of 46 days. We found that all three treatment strategies reduced iron concentrations in both heart and kidney, as compared to a baseline group that was terminated at start of study. None of the treatments were able to reduce liver iron but all three prevented further iron deposition in the liver as compared to baseline. It's possible that the length of phlebotomy treatment is not sufficient to result in iron removal from liver. Treatment with PN23114 redistributed the excess iron into spleen and duodenum, thereby significantly elevating spleen iron concentration, while co-treatment of PN23114 and phlebotomy did not result in marked iron sequestration in spleen. Serum ferritin was reduced in all three treatment groups, the group that received the PN23114 and phlebotomy co-treatment showed the largest reduction. Serum iron was normalized with PN23114 treatment and with co-treatment with PN23114 and phlebotomy. Phlebotomy treatment was not able to lower serum iron to normal levels. Our data overall indicate that combining hepcidin mimetic treatment along with phlebotomy may be more effective in quickly lowering TSAT% and labile iron, and thereby quickly reversing tissue iron deposition in specific organs. Titration of rusfertide to the desired clinical effect may be effective in combination with phlebotomy during the induction phase of clinical management to reduce the frequency and duration of phlebotomy treatment as well as lower the lingering high TSAT% levels.

S1386 The National Trends and Hospitalizations of Patients with Hereditary Hemochromatosis in the United States: Insights From the National Inpatient Sample

Introduction: Hereditary hemochromatosis (HH) is a disorder of increased intestinal iron absorption leading to total body iron overload. Although it is among the most common genetic diseases globally, no large-scale nationwide data is available regarding HH-related hospitalizations in the United States. Our study aimed to find on a national level the demographics of the patients with HH, inpatient mortality, and resource utilization using the national inpatient database (NIS). Methods: We queried the nationwide inpatient (NIS) 2016-2019 databases using the ICD-10 CM codes to identify all the patients hospitalized with hereditary hemochromatosis (HH). We excluded patients under 18 years. The primary outcome of our study was to do an exploratory analysis and determine the baseline demographic characteristics of patients admitted with HH. The secondary outcomes included in-hospital mortality, length of stay (LOS), hospitalization cost, and outcomes. Results: A total of 196 adult patients with HH were admitted in the United States with a mean age of 59.3 years. The majority of the patients were males (55%) and Caucasians (97.2%). The mean length of stay was 6 days, and a total of 10 patients (0.5%) died in the hospital. Medicare (47.2%) was the most common insurance, and most of the patients were admitted to large tertiary care hospitals. Patients with concomitant Alcoholic Liver Disease (ALD) had greater LOS (7.5 days vs. 6 days) than patients without ALD. The rest of the demographics are shared in the Table. Conclusion: Our study demonstrated that most of the patients admitted with HH are Caucasians and males. The mean LOS is 6 days. The total mean cost of hospitalizations is $21,763.The HH patients with concomitant Hepatitis C and Alcoholic Liver Disease have higher healthcare utilization and worse outcomes than other patients. So, patients with HH should be screened for Hepatitis C and alcoholic Liver disease to improve the outcomes for these patients. Table 1. - Baseline patient and hospital characteristics and outcomes for HH-related hospitalizations Patient Characteristics Hereditary Hemochromatosis (HH) No. of patients 196 Male (%) 109 (55.7%) Mean age, (SD) years 59.38 Race [N, %] Caucasian 190 (97.04%) African American 0 Hispanic 0 Asian 6 (2.96%) Charlson Comorbidity Index Score [N, %] 0 56 (28.71%) 1 47 (24.07%) 2 19 (9.56%) 3 or more 74 (37.63%) Median Income (Zip Codes) [N, %] $1-$38,999 25 (12.97%) $39,000-$47,999 48 (24.29%) $48,000-$62,999 38 (19.17%) >$ 63,000 85 (43.54%) Insurance Provider [N, %] Medicare 93 (47.28%) Medicaid 14 (7.03%) Private 84 (42.94%) Others 2.7% Hospital Characteristics Hospital teaching Status [N, %] Non-Teaching 94 (48.05%) Teaching 102 (51.94%) Hospital Bed Size [N, %] Small 35 (17.79%) Medium 63 (32.07%) Large 98.2 (50.12%) Hospital Location [N, %] Rural 4 (1.8%) Urban 192 (98.11%) Outcomes HH HH & Hep C HH & ALD Mortality, no. % 10 (0.5%) 10(50%) 0 Length of Stay (SD) 6 5.9 7.5 Hospitalization cost (SD) $21,763 $38,161 $43,962

Hereditary hemochromatosis: Temporal trends, sociodemographic characteristics, and independent risk factor of hepatocellular cancer - nationwide population-based study.

BACKGROUNDHereditary hemochromatosis (HH) has an increased risk of hepatocellular cancer (HCC) both due to genetic risks and iron overload as iron overload can be carcinogenic; HH impacts the increasing risk of HCC, not only through the development of cirrhosis but concerning hepatic iron deposition, which has been studied further recently. AIMTo evaluate HH yearly trends, patient demographics, symptoms, comorbidities, and hospital outcomes. The secondary aim sheds light on the risk of iron overload for developing HCC in HH patients, independent of liver cirrhosis complications. The study investigated HH (without cirrhosis) as an independent risk factor for HCC.METHODSWe analyzed data from National Inpatient Sample (NIS) Database, the largest national inpatient data collection in the United States, and selected HH and HCC cohorts. HH was first defined in 2011 International Classification of Disease - 9th edition (ICD-9) as a separate diagnosis; the HH cohort is extracted from January 2011 to December 2019 using 275.01 (ICD-9) and E83.110 (ICD-10) diagnosis codes of HH. Patients were excluded from the HH cohort if they had a primary or secondary diagnostic code of cirrhosis (alcoholic, non-alcoholic, and biliary), viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), and non-alcoholic steatohepatitis (NASH). We removed these patients from the HH cohort to rule out bias or ICD-10 diagnostic errors. The HCC cohort is selected from January 2011 to December 2019 using the ICD-9 and ICD-10 codes of HCC. We selected a non-HCC cohort with the 1:1 fixed ratio nearest neighbor (greedy) propensity score method using the patients' age, gender, and race. We performed multivariate analysis for the risk factors of HCC in the HCC and non-HCC matched cohort. We further analyzed HH without cirrhosis (removing HH patients with a diagnosis of cirrhosis) as an independent risk factor of HCC after adjusting all known risk factors of HCC in the multivariate model. RESULTSDuring the 2011-2019 period, a total of 18031 hospitalizations with a primary or secondary diagnosis of HH (excluding liver diseases) were recorded in the NIS database. We analyzed different patients’ characteristics, and we found increments in inpatient population trend with a Ptrend < 0.001 and total hospital cost of care trend from $42957 in 2011 to $66152 in 2019 with a Ptrend < 0.001 despite no change in Length of Stay over the last decade. The multivariate analyses showed that HH without cirrhosis (aOR, 28.8; 95%CI, 10.4–80.1; P < 0.0001), biliary cirrhosis (aOR, 19.3; 95%CI, 13.4–27.6; P < 0.0001), non-alcoholic cirrhosis (aOR, 17.4; 95%CI, 16.5–18.4; P < 0.0001), alcoholic cirrhosis (aOR, 16.9; 95%CI, 15.9–17.9; P < 0.0001), hepatitis B (aOR, 12.1; 95%CI, 10.85–13.60; P < 0.0001), hepatitis C (aOR, 8.58; 95%CI, 8.20–8.98; P < 0.0001), Wilson disease (aOR, 4.27; 95%CI, 1.18–15.41; P < 0.0001), NAFLD or NASH (aOR, 2.96; 95%CI, 2.73–3.20; P < 0.0001), alpha1-antitrypsin deficiency (aOR, 2.10; 95%CI, 1.21–3.64; P < 0.0001), diabetes mellitus without chronic complications (aOR, 1.17; 95%CI, 1.13–1.21; P < 0.0001), and blood transfusion (aOR, 1.80; 95%CI, 1.69–1.92; P < 0.0001) are independent risk factor for liver cancer.CONCLUSIONOur study showed an increasing trend of in-hospital admissions of HH patients in the last decade. These trends were likely related to advances in diagnostic approach, which can lead to increased hospital utilization and cost increments. Still, the length of stay remained the same, likely due to a big part of management being done in outpatient settings. Another vital part of our study is the significant result that HH without cirrhosis is an independent risk factor for HCC with adjusting all known risk factors. More prospective and retrospective large studies are needed to re-evaluate the HH independent risk in developing HCC.

170 Non-melanoma skin cancer and hereditary hemochromatosis: A retrospective cohort study

Hereditary hemochromatosis (HH) is a genetic disease of altered iron homeostasis. HH causes skin hyperpigmentation and various diseases, such as hepatocellular carcinoma via oxidative stress. Although oxidative damage also plays a role in the pathogenesis of non-melanoma skin cancer (NMSC), the link between HH and NMSC remains unknown. Data on HH patients with skin neoplasms and controls from 1980 to 2021 matched by age, sex, and race were extracted. HH carriers without disease and/or those without pathology-proven skin neoplasms were excluded.

Analysis of The Left Atrial Function Using Two-Dimensional Strain in Patients with Recent Diagnosis of Hereditary Hemochromatosis.

Hereditary Hemochromatosis (HH) is a genetic condition associated with a systemic iron overload. Heart failure is an important cause of mortality. It has been demonstrated early stages of systolic and diastolic left ventricular dysfunction in previous studies. The aim of the study is to compare the left atrial (LA) function between asymptomatic HH patients and a control group using 2D speckle tracking. Prospective study. LA strain, LA strain rate and LA volumetric parameters during the reservoir, conduit and contraction phases were studied. The LA Stiffness Index was calculated by the ratio between E/e and LA reservoir strain. 30 patients with HH (90% males, 47 ± 18 years old) and 30 healthy controls (85% males, 45 ± 13 years old) were included. LA volume was similar in both groups. No differences were observed in LA ejection fraction (EF), LA passive EF and LA active ejection fraction between both groups. On the contrary, the HH group had lower LA strain during the reservoir (31.5 ± 6.5% vs 38.3 ± 7.9%; P=0.002), and conduit phases (-18 ± 7% vs -23.3 ± 6.4%; P=0.01) and lower LA conduit strain rate (-1.7 ± 0.7 seg-1 vs -2.1 ± 0.5 seg-1; P=0.02) than controls. The LA stiffness index was significantly higher in the HH group (0.25 ± 0.9 vs 0.19 ± 0.6; P=0.01) Early abnormalities in the LA function could be detected by using 2D speckle tracking study despite no evidence of changes in atrial size or volumetric parameters.

Hereditary hemochromatosis: data from a single center Copenhagen cohort

Objectives We aimed to describe a cohort of hereditary hemochromatosis (HH) patients from a single urban center in Copenhagen. Methods Retrospectively, data from patients with HH from the years 2009–2020 were collected. Results A total of 203 patients was recorded. Males constituted 65.0% of the patients. Homozygous HH (HHH)/compound heterozygous HH (CHH) accounted for 69.4%/30.6%. HHH patients had significantly higher ferritin and transferrin saturation (TS) levels at debut than CHH patients. Fifty-five HHH patients (39.0%) had ferritin >1000 ug/L versus 9 (14.5%) in the CHH group (p < .001). Age at debut did not differ between female and male patients. Ferritin (but not TS) levels were significantly higher in male patients. The proportion of patients with ferritin >1000 did not differ between males and females. One-hundred patients (49.3%) had one or more symptoms at the time of diagnosis; arthralgias of the metacarpophalangeal joints and/or ankles (n = 46 (22.7%)), fatigue (n = 67 (33.0%)) and decreased libido (n = 20 (9.9%)). The proportion of patients with symptoms did not differ between HHH and CHH or between male and female patients. Severe organ complications (cardiomyopathy, late onset type 1 diabetes or cirrhosis) were present in 14 patients (6.9%). Conclusions We report a high proportion of compound HH, constituting almost one-third of patients. We found that the proportion of patients with symptoms did not differ between HHH and CHH and recommend that CHH should be treated and examined in the same way as HHH.

Can 2D speckle tracking echocardiography be useful in venesection therapy monitoring in hereditary hemochromatosis patients?

Abstract Funding Acknowledgements Type of funding sources: None. Background. Hereditary hemochromatosis (HH) is a widespread genetic disease. Abnormally increased intestinal iron absorption and accelerated recycling of iron lead to progressive body iron accumulation and the generation of oxidative stress in tissues. Venesection is the primary treatment of such patients. Based on the fact that two-dimensional speckle tracking echocardiography (2D STE) can evaluate left ventricle (LV) dysfunction more accurately and earlier than conventional echocardiography, the purpose of our study was to check whether it could be helpful in venesection therapy monitoring. Methods. We prospectively enrolled 20 patients with genetically confirmed HH. Classic echocardiographic and 2D STE parameters (GE VIVID E9, EchoPAC v202) were analyzed at the moment of diagnosis, and after three years of treatment with venesection; 20 healthy age- and sex-matched persons constituted the control group. Results. The HH patients had all standard echo parameters within the normal range at the first and second examinations. The rotation parameters were initially worse than in healthy people at the first visit and significantly increased after three years of treatment. The radial strain after the treatment was significantly better for the apex but not for basal LV, apart from the epicardial layer (known as the layer of iron overload in the heart). Global longitudinal strain (GLS), significantly lower than in healthy people at the first visit, did not change within the treatment (Table). Conclusions. Venesection leads to significant improvement in the rotation function of LV and increases radial strain mainly in the epicardium, which seems to help monitor the treatment and guide the intensity of venesections. GLS, which is known as a parameter for early detection of heart abnormalities in asymptomatic HH patients, did not increase within the treatment and could reveal irreversible changes in LV. Abstract Figure.

Abstract 13633: Cardiac Arrhythmias in Hospitalized Patients With Hereditary Hemochromatosis

Introduction: Cardiac iron overload in Hereditary Hemochromatosis (HH) can lead to conduction disturbances, arrhythmias, and rarely, cardiac arrest. There is a paucity of data on HH and the burden of cardiac arrhythmias and its repercussions. Hypothesis: To determine baseline characteristics of HH patients with and without arrhythmias, frequency of subtypes of arrhythmias, and related in-hospital outcomes such as mortality, length of stay (LOS), and total hospital costs. Methods: An HH-related adult hospitalizations with or without arrhythmias were analyzed using the National Inpatient Sample database from 2016 to 2018. We used propensity score matching to balance out the differences in baseline characteristics among the 2 groups. Results: Out of 10455 HH hospitalizations, 2525 (24.2 %) had concurrent arrhythmias. The arrhythmia cohort consisted of older patients (mean age, 68.9 vs 59.8 years), predominantly males (71.1% vs 61.5%), and Caucasians (92.5% vs 89.3%) compared to those without arrhythmia (p&lt;.001). HH patients with arrhythmias had an almost 3-fold higher prevalence of congestive heart failure (11.5% vs 3.7%) and coronary artery disease (33.3% vs 12.2%) (p&lt;.001). Atrial fibrillation (AF) (73.3%) was the most common arrhythmia followed by atrial flutter (8.3%), ventricular tachycardia (8.1%), and supraventricular tachycardia (7.7%). The arrhythmia cohort had higher mortality (6.7% vs. 2.3%) and mean hospital cost ($ 25,957 vs $16,742) as compared to the non-arrhythmia cohort ( P &lt; .001). Mean LOS (6.7 vs 5.7 days, p=0.007) was comparable between the groups. Conclusions: Our study suggests a high burden of arrhythmia in HH-hospitalizations with AF being the most common arrhythmia. The arrhythmia cohort had significantly higher in-hospital mortality, and hospitalization cost. This warrants further studies to better delineate pathogenesis and early diagnosis and treatment strategies specifically curated for HH-associated arrhythmias.

Rusfertide (PTG-300), a Hepcidin Mimetic, Maintains Liver Iron Concentration in the Absence of Phlebotomies in Patients with Hereditary Hemochromatosis

▪Introduction: Patients with hereditary hemochromatosis (HH) require continued phlebotomies to limit end-organ damage. Approximately 25% of patients in maintenance felt receiving phlebotomies was “inconvenient” or “very inconvenient” (Brisott et al, 2011). Patient compliance with phlebotomies generally declines with time (Hicken et al, 2003), and therapeutic phlebotomies may not be medically suitable for some HH patients. Rusfertide, a peptide mimetic of hepcidin, is an effective regulator of iron distribution and utilization that has demonstrated control of iron in an animal model of HH.Methods: We conducted an open-label, dose-finding efficacy study that investigated subcutaneous rusfertide in HH patients on a stable phlebotomy regimen of 0.25 to 1 phlebotomy per month for at least 6 months. Patients with clinical laboratory abnormalities and those receiving iron chelation therapy or erythrocytapheresis were excluded. Subjects received individually titrated rusfertide doses once or twice a week to maintain transferrin saturation (TSAT) below 45% and were followed for 6 months. Study measures included TSAT, serum iron, transferrin and ferritin, liver iron concentration (LIC) measured by MRI, and adverse events (AEs).Results: Sixteen subjects (10 male/6 female) were enrolled. Mean age and weight were 62.5 years and 88.1 kg, respectively. LIC values were maintained at pre-study levels, with minimal use of phlebotomies during the duration of the study (Figure 1A). Average pre-study phlebotomy rate was 0.27 phlebotomies/month compared to 0.03 phlebotomies/month during the study (p<0.0001; Figure 1B). There was a dose- and concentration-dependent decrease in serum iron and TSAT (Figure 2A and 2B). Transferrin levels were relatively constant over the course of the study. There were no notable changes in hematological parameters such as hematocrit, erythrocytes, leucocytes, or platelets. Rusfertide was generally well tolerated. Adverse events reported in 2 or more subjects included diarrhea, fatigue, injection site reactions (erythema, induration, pain, pruritis), dizziness, and headache.Conclusions: Rusfertide demonstrated a pharmacodynamic effect in reducing TSAT and serum iron, with corresponding significant reduction in the number of phlebotomies, and with LIC maintained at pre-study levels with minimal use of phlebotomies. These data indicate rusfertide was well tolerated in patients with HH and controls LIC, supporting development of rusfertide as a potential treatment for HH. [Display omitted] DisclosuresKowdley: PTG: Consultancy, Research Funding. Modi: Protagonist Therapeutics: Current Employment. Valone: Protagonist Therapeutics: Current Employment, Current equity holder in publicly-traded company. Gupta: Protagonist Therapeutics: Current Employment.

S2901 Yersinia enterocolitica Liver Abscesses as an Atypical Presentation of Hereditary Hemochromatosis

Introduction: Hereditary hemochromatosis typically presents with organ dysfunction due to iron overload. Yersinia enterocolitica is an iron-utilizing microbe which hereditary hemochromatosis patients are predisposed to. We present an atypical presentation of hereditary hemochromatosis that was uncovered by liver abscesses caused by yersinia enterocolitica. This case highlights the importance of considering hereditary hemochromatosis in the setting of yersinia enterocolitica infection. Case Description/Methods: A 75 year old male with a PMH of diabetes mellitus, congestive heart failure, and complete heart block presented two months after pacemaker placement with nausea, anorexia, and subjective fevers. Physical exam was benign from a gastrointestinal standpoint. CT abdomen and pelvis showed multiple hepatic lesions. Biopsy confirmed abscess, and cultures grew yersinia enterocolitica. Initial ferritin was elevated above 4500. Blood cultures remained negative. Treatment with ceftriaxone and metronidazole was complicated by severe sepsis before resolution of abscesses were confirmed by CT. Post-infection, repeat ferritin remained elevated over 1000 with transferrin saturation elevated above 79%. Genetic testing confirmed homozygous C282Y gene mutations. The patient was advised to follow-up for possible phlebotomy. Discussion: Our case highlights that liver abscesses due to yersinia enterocolitica should provoke an investigation for hereditary hemochromatosis. Hereditary hemochromatosis likely contributed to multiple disease processes in our patient including heart failure, conduction disturbances, and diabetes mellitus. Early diagnosis of hereditary hemochromatosis has the potential to avoid later disease complications in patients and their families.Figure 1.: CT scan of liver abscesses from yersinia enterocolitica infection.

The Role of the Trabecular Bone Score in the Assessment of Osteoarticular Disorders in Patients with HFE-Hemochromatosis: A Single-Center Study from Poland.

Type 1 hereditary hemochromatosis (HH) is an autosomal, recessive genetic entity with systemic iron overload. Iron homeostasis disorders develop as a result of HFE gene mutations, which are associated with hepcidin arthropathy or osteoporosis and may cause permanent disability in HH patients despite a properly conducted treatment with phlebotomies. In this study, selected parameters of calcium and phosphate metabolism were analyzed in combination with the assessment of bone mineral density (BMD) disorders in patients from northern Poland with clinically overt HFE-HH. BMD was determined by a dual-energy X-ray absorptiometry (DXA) test with the use of the trabecular bone score (TBS) function. The study included 29 HH patients (mean age = 53.14 years) who were compared with 20 healthy volunteers. A significantly lower TBS parameter and serum 25-OH-D3 concentration, a higher concentration of intact parathormone and more a frequent occurrence of joint pain were found in HH patients compared with the control group. In HH patients, the diagnosis of liver cirrhosis was associated with lower serum 25-OH-D3 and osteocalcin concentrations. In HH, DXA with the TBS option is a valuable tool in the early assessment of the bone microarchitecture and fracture risk. A supplementation of vitamin D, monitoring its concentration, should be considered especially in HH patients with liver damage and liver cirrhosis.

Postoperative Complications in Patients With Hereditary Hemochromatosis Undergoing Total Joint Arthroplasty: A Matched Cohort Analysis.

The purpose of this study is to determine differences in the rates of 90-day postoperative complications and 2- and 5-year surgical outcomes between patients with and without hereditary hemochromatosis (HH) after total joint arthroplasty (TJA). Patients who underwent primary total hip arthroplasty (THA) or total knee arthroplasty (TKA) from 2010 to 2018 were identified in a national database (PearlDiver Technologies) using Current Procedural Terminology and International Classification of Diseases-9/10 codes. Patients with a history of HH were identified within the THA and TKA cohorts and matched with non-HH patients based on age, sex, Charlson Comorbidity Index, smoking status, and obesity (body mass index > 30). Ninety-day medical complications assessed included renal failure, arrhythmia, bleeding complications, blood transfusion, pneumonia, stroke, deep vein thrombosis, liver failure, heart failure, pulmonary embolism, sepsis, surgical site infection, wound dehiscence, readmission rate, and death. Two- and 5-year surgical complications assessed included all-cause revision, prosthetic joint infection, implant loosening, joint stiffness, and manipulation under anesthesia. All complications were analyzed using bivariate analysis and logistic regression, with significance set at P < 0.05. Compared with non-HH patients, patients with HH had higher rates of stiffness at 2 and 5 years after THA (all, P < 0.001), as well as higher rates of aseptic loosening at 5 years after TKA (P = 0.036). However, patients with HH undergoing THA and TKA had no notable difference in 90-day postoperative complications when compared with non-HH patients. Compared with non-HH patients, patients with HH undergoing TJA were shown to have worse 2- and 5-year surgical outcomes, without any increased risk of 90-day medical complications. These findings may be useful for surgical decision making for patients with HH undergoing TJA. This study addresses a paucity in the current literature concerning the complication profile in HH patients with destructive joint arthropathy undergoing joint arthroplasty surgery.

Pathogenesis, Diagnosis, and Clinical Implications of Hereditary Hemochromatosis—The Cardiological Point of View

Hereditary hemochromatosis (HH) is a genetic disease leading to excessive iron absorption, its accumulation, and oxidative stress induction causing different organ damage, including the heart. The process of cardiac involvement is slow and lasts for years. Cardiac pathology manifests as an impaired diastolic function and cardiac hypertrophy at first and as dilatative cardiomyopathy and heart failure with time. From the moment of heart failure appearance, the prognosis is poor. Therefore, it is crucial to prevent those lesions by upfront therapy at the preclinical phase of the disease. The most useful diagnostic tool for detecting cardiac involvement is echocardiography. However, during an early phase of the disease, when patients do not present severe abnormalities in serum iron parameters and severe symptoms of other organ involvement, heart damage may be overlooked due to the lack of evident signs of cardiac dysfunction. Considerable advancement in echocardiography, with particular attention to speckle tracking echocardiography, allows detecting discrete myocardial abnormalities and planning strategy for further clinical management before the occurrence of substantial heart damage. The review aims to present the current state of knowledge concerning cardiac involvement in HH. In addition, it could help cardiologists and other physicians in their everyday practice with HH patients.

The effect of the flavonol rutin on serum and liver iron content in a genetic mouse model of iron overload.

The flavonol rutin has been shown to possess antioxidant and iron chelating properties in vitro and in vivo. These dual properties are beneficial as therapeutic options to reduce iron accumulation and the generation of reactive oxygen species (ROS) resultant from excess free iron. The effect of rutin on iron metabolism has been limited to studies performed in wildtype mice either injected or fed high-iron diets. The effect of rutin on iron overload caused by genetic dysregulation of iron homoeostasis has not yet been investigated. In the present study we examined the effect of rutin treatment on tissue iron loading in a genetic mouse model of iron overload, which mirrors the iron loading associated with Type 3 hereditary haemochromatosis patients who have a defect in Transferrin Receptor 2 (TFR2). Male TFR2 knockout (KO) mice were administered rutin via oral gavage for 21 continuous days. Following treatment, iron levels in serum, liver, duodenum and spleen were assessed. In addition, hepatic ferritin protein levels were determined by Western blotting, and expression of iron homoeostasis genes by quantitative real-time PCR. Rutin treatment resulted in a significant reduction in hepatic ferritin protein expression and serum transferrin saturation. In addition, trends towards decreased iron levels in the liver and serum, and increased serum unsaturated iron binding capacity were observed. This is the first study to explore the utility of rutin as a potential iron chelator and therapeutic in an animal model of genetic iron overload.