Long-term survival in patients with hereditary hemochromatosis
Abstract
BACKGROUND & AIMS: The course of hereditary hemochromatosis may depend on the degree of iron overload and the time of therapeutic intervention. This analysis evaluates the impact of early diagnosis and iron removal on survival and complications in hereditary hemochromatosis. METHODS: A Cohort of 251 patients with hemochromatosis was followed up for 14.1 +/- 6.8 years. RESULTS: Survival was reduced in the total group of patients when compared with a matched normal population. Survival in noncirrhotic and nondiabetic patients and in patients diagnosed between 1982 and 1991 was identical with rates expected. Survival was reduced in patients with severe iron overload vs. those with less severe overload. The percentage of early diagnoses increased threefold between 1947 and 1969 to that between 1970 and 1981; there was only a further 20%-25% increase in the last decade. Deaths caused by liver cancer, cardiomyopathy, liver cirrhosis, and diabetes mellitus were increased as compared with expected rates. Liver cancers were associated with cirrhosis and amount of mobilizable iron but not with hepatitis B or C markers. CONCLUSIONS: Prognosis of hemochromatosis and most of its complications, including liver cancer, depend on the amount and duration of iron excess. Early diagnosis and therapy largely prevent the adverse consequences of iron overload. (Gastroenterology 1996 Apr;110(4):1107-19)
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Pharmacological approaches for targeting lysosomes to induce ferroptotic cell death in cancer
2024, Cancer LettersLysosomes are crucial organelles responsible for the degradation of cytosolic materials and bulky organelles, thereby facilitating nutrient recycling and cell survival. However, lysosome also acts as an executioner of cell death, including ferroptosis, a distinctive form of regulated cell death that hinges on iron-dependent phospholipid peroxidation. The initiation of ferroptosis necessitates three key components: substrates (membrane phospholipids enriched with polyunsaturated fatty acids), triggers (redox-active irons), and compromised defence mechanisms (GPX4-dependent and -independent antioxidant systems). Notably, iron assumes a pivotal role in ferroptotic cell death, particularly in the context of cancer, where iron and oncogenic signaling pathways reciprocally reinforce each other. Given the lysosomes’ central role in iron metabolism, various strategies have been devised to harness lysosome-mediated iron metabolism to induce ferroptosis. These include the re-mobilization of iron from intracellular storage sites such as ferritin complex and mitochondria through ferritinophagy and mitophagy, respectively. Additionally, transcriptional regulation of lysosomal and autophagy genes by TFEB enhances lysosomal function. Moreover, the induction of lysosomal iron overload can lead to lysosomal membrane permeabilization and subsequent cell death. Extensive screening and individually studies have explored pharmacological interventions using clinically available drugs and phytochemical agents. Furthermore, a drug delivery system involving ferritin-coated nanoparticles has been specifically tailored to target cancer cells overexpressing TFRC. With the rapid advancements in understandings the mechanistic underpinnings of ferroptosis and iron metabolism, it is increasingly evident that lysosomes represent a promising target for inducing ferroptosis and combating cancer.
Rusfertide for the treatment of iron overload in HFE-related haemochromatosis: an open-label, multicentre, proof-of-concept phase 2 trial
2023, The Lancet Gastroenterology and HepatologyHereditary haemochromatosis protein (HFE)-related haemochromatosis, an inherited iron overload disorder caused by insufficient hepcidin production, results in excessive iron absorption and tissue and organ injury, and is treated with first-line therapeutic phlebotomy. We aimed to investigate the efficacy and safety of rusfertide, a peptidic mimetic of hepcidin, in patients with HFE-related haemochromatosis.
This open-label, multicentre, proof-of-concept phase 2 trial was done across nine academic and community centres in the USA and Canada. Adults (aged ≥18 years) with HFE-related haemochromatosis on a stable therapeutic phlebotomy regimen (maintenance phase) for at least 6 months before screening and who had a phlebotomy frequency of at least 0·25 per month (eg, at least three phlebotomies in 12 months or at least four phlebotomies in 15 months) and less than one phlebotomy per month, with serum ferritin of less than 300 ng/mL and haemoglobin of more than 11·5 g/dL, were eligible. Patients initiated 24 weeks of subcutaneous rusfertide treatment within 7 days of a scheduled phlebotomy at 10 mg once weekly. Rusfertide doses and dosing schedules could be adjusted to maintain serum transferrin iron saturation (TSAT) at less than 40%. During rusfertide treatment, investigators were to consider the need for phlebotomy when the serum ferritin and TSAT values exceeded the patient's individual pre-phlebotomy serum ferritin and TSAT values. No primary endpoint or testing hierarchy was prespecified. Prespecified efficacy endpoints included the change in the frequency of phlebotomies; the proportion of patients achieving phlebotomy independence; change in serum iron, TSAT, serum transferrin, serum ferritin, and liver iron concentration (LIC) as measured by MRI; and treatment-emergent adverse events (TEAEs). The key efficacy analyses for phlebotomy rate and LIC were conducted by use of paired t tests in the intention-to-treat population, defined as all patients who received any study drug and who had pretreatment and at least one post-dose measurement. We included all participants who received at least one dose of rusfertide in the safety analyses. This trial is closed and completed and is registered with ClinicalTrials.gov, NCT04202965.
Between March 11, 2020, and April 23, 2021, 28 patients were screened and 16 (ten [63%] men and six [38%] women) were enrolled. 16 were included in analyses of phlebotomy endpoints and 14 for the LIC endpoint. 12 (75%) patients completed 24 weeks of treatment. The mean number of phlebotomies was significantly reduced during the 24-week rusfertide treatment (0·06 phlebotomies [95% CI –0·07 to 0·20]) compared with 24 weeks pre-study (2·31 phlebotomies [95% CI 1·77 to 2·85]; p<0·0001). 15 (94%) of 16 patients were phlebotomy-free during the treatment period. Mean LIC in the 14 patients in the intention-to-treat population was 1·4 mg iron per g dry liver weight (95% CI 1·0 to 1·8) at screening and 1·1 mg iron per g dry liver weight (95% CI 0·9 to 1·3) at the end of treatment (p=0·068). Mean TSAT was 45·3% (95% CI 33·2 to 57·3) at screening, 36·7% (24·2 to 49·2) after the pretreatment phlebotomy, 21·8% (15·8 to 27·9) 24 h after the first dose of rusfertide, 40·4% (27·1 to 53·8) at the end of treatment, and 32·6% (25·0 to 40·1) over the treatment duration. Mean serum iron was 24·6 μmol/L (95% CI 18·6 to 30·6), 20·1 μmol/L (14·8 to 25·3), 11·9 μmol/L (9·2 to 14·7), 22·5 μmol/L (15·9 to 29·1), and 19·0 μmol/L (15·3 to 22·6) at these same timepoints, respectively. Mean serum ferritin was 83·3 μg/L (52·2 to 114.4), 65·5 μg/L (32·1 to 98·9), 62·8 μg/L (33·8 to 91·9), 150·0 μg/L (86·6 to 213.3), and 94·3 μg/L (54·9 to 133.6) at these same timepoints, respectively. There were only minor changes in serum transferrin concentration. 12 (75%) patients had at least one TEAE, the most common of which was injection site pain (five [31%] patients). All TEAEs were mild or moderate in severity, except for a serious adverse event of pancreatic adenocarcinoma, which was considered severe and unrelated to treatment and was pre-existing and diagnosed 21 days after starting rusfertide treatment.
Rusfertide prevents iron re-accumulation in the absence of phlebotomies and could be a viable therapeutic option for selected patients with haemochromatosis.
Protagonist Therapeutics.
Hereditary hemochromatosis
2023, Comprehensive Guide to Hepatitis AdvancesHereditary hemochromatosis is an endocrine liver disease caused by a deficit in the synthesis or activity of the hormone hepcidin, leading to increased iron absorption and progressive tissue overload and organ damage. Typical manifestations include liver disease, arthropathy and osteoporosis, diabetes, hypogonadotropic hypogonadism, and heart disease. Hemochromatosis is most frequent in Europeans, where it is caused by homozygosity for the p.C282Y variant of HFE (allelic frequency 0.01–0.08) and is more commonly expressed in males after the fourth decade, especially in the presence of at-risk alcohol intake, fatty liver, and dyserythropoiesis. Pathogenic variants in other genes influencing hepcidin are less frequently responsible for this condition. Treatment is based on iron depletion, by phlebotomy or erythrocytapheresis/chelators in those who are intolerant. Iron depletion improves organ damage and normalizes life expectancy in those diagnosed at earlier stages, but hepatocellular carcinoma risk remains high in cirrhotics and arthropathy compromises life quality at later stages.
Disorders of Iron Overload
2023, MacSween's Pathology of the Liver, Eighth EditionIron disorders of the liver are best understood in the context of normal iron metabolism, so the biology of iron metabolism and homeostasis is reviewed. Mutations that lead to dysregulation of normal iron homeostasis are the basis for genetic iron overload. These mutations and their clinical and histological manifestations are examined, with a focus on information relevant to diagnostic surgical pathology. Secondary iron is also discussed, including its many causes and the histological manifestations.
A digital image-based flow-batch analyzer for iron speciation in tomato
2023, Journal of Food Composition and AnalysisCitation Excerpt :Its deficiency is related, in most cases, to the cause of anemia. On the other hand, high levels of iron have been associated with an increased risk of cancer, heart disease, arthritis, diabetes, and endocrine problems (Niederau et al., 1996). The chemical and biological activity and toxicity of iron are distinct for each oxidation state (Paluch et al., 2017).
In this study, a simple and sensitive digital image-based flow-batch analyzer (DIB-FBA) was developed for the chemical speciation of iron in tomato samples. The Fe(II) determination is based on the Fe(II)/1,10-phenanthroline reaction. Total iron was determined by reducing all Fe(III) to Fe(II) with ascorbic acid, and Fe(III) was calculated by subtracting Fe(II) content from the total iron content. Digital images were obtained using a webcam, reducing costs and simplifying the instrumentation. RGB data was extracted using software written in ActionScript 3.0, and the B component was employed to build the analytical curve. Samples of different tomato types and certified reference material were successfully analyzed using the DIB-FBA, which presented satisfactory performance parameters such as working range (0.1–1.0 mg L−1), LOD (2.33 μg L–1), LOQ (7.72 μg L–1), RSD (0.05% to 0.45%), analytical frequency (64 h–1), sample (150 µL) and waste (1.9 mL) volume. Furthermore, according to paired t-test at a 95% confidence level, no significant differences between the results from the DIB-FBA and those from the reference methods were found. The advantageous combination of digital image and flow automation provided by the DIB-FBA can be further explored for the speciation of other metals in diverse food samples.
Indices of iron homeostasis in asymptomatic subjects with HFE mutations and moderate ferritin elevation during iron removal treatment
2022, Blood Cells, Molecules, and DiseasesWe analysed iron biomarkers and their relationships in 30 subjects with HFE mutations and moderate hyperferritinaemia undergoing iron removal at our blood donation centre.
Body mass index (BMI) and liver enzymes were assessed. Serum iron (SI), ferritin, transferrin saturation (TSAT), hepcidin and non-transferrin bound iron (NTBI) were measured serially.
Seventeen subjects had p.C282Y/p.C282Y, nine p.C282Y/p.H63D, four p.H63D/p.H63D. Median age (p = 0.582), BMI (p = 0.500) and ferritin (p = 0.089) were comparable.
At baseline, 12/17 p.C282Y/p.C282Y and 2/9 p.C282Y/p.H63D had measurable NTBI (p = 0.003). The p.C282Y/p.C282Y had higher TSAT (p < 0.001), lower hepcidin (p = 0.031) and hepcidin/ferritin ratio (p = 0.073). After treatment, iron indices were similar among groups, except TSAT (higher in p.C282Y/p.C282Y; p = 0.06).
Strong relationships were observed between ferritin and TSAT (R = 0.71), NTBI and TSAT (R = 0.61), NTBI and SI (R = 0.54) in p.C282Y/p.C282Y. Hepcidin correlated weakly with ferritin in p.C282Y/p.C282Y (R = 0.37) but strongly in p.C282Y/p.H63D (R = 0.66) and p.H63D/p.H63D (R = 0.72), while relationships with TSAT were weak (R = 0.27), moderate (R = 0.55) and strong (R = 0.61), respectively.
Low penetrance p.C282Y/p.C282Y phenotype displays hepcidin dysregulation and biochemical risk for iron toxicity.