{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T02:09:05Z","timestamp":1791598145333,"version":"4.3.4"},"reference-count":130,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2024,2,25]],"date-time":"2024-02-25T00:00:00Z","timestamp":1708819200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Hemochromatosis represents clinically one of the most important genetic storage diseases of the liver caused by iron overload, which is to be differentiated from hepatic iron overload due to excessive iron release from erythrocytes in patients with genetic hemolytic disorders. This disorder is under recent mechanistic discussion regarding ferroptosis, reactive oxygen species (ROS), the gut microbiome, and alcohol abuse as a risk factor, which are all topics of this review article. Triggered by released intracellular free iron from ferritin via the autophagic process of ferritinophagy, ferroptosis is involved in hemochromatosis as a specific form of iron-dependent regulated cell death. This develops in the course of mitochondrial injury associated with additional iron accumulation, followed by excessive production of ROS and lipid peroxidation. A low fecal iron content during therapeutic iron depletion reduces colonic inflammation and oxidative stress. In clinical terms, iron is an essential trace element required for human health. Humans cannot synthesize iron and must take it up from iron-containing foods and beverages. Under physiological conditions, healthy individuals allow for iron homeostasis by restricting the extent of intestinal iron depending on realistic demand, avoiding uptake of iron in excess. For this condition, the human body has no chance to adequately compensate through removal. In patients with hemochromatosis, the molecular finetuning of intestinal iron uptake is set off due to mutations in the high-FE2+ (HFE) genes that lead to a lack of hepcidin or resistance on the part of ferroportin to hepcidin binding. This is the major mechanism for the increased iron stores in the body. Hepcidin is a liver-derived peptide, which impairs the release of iron from enterocytes and macrophages by interacting with ferroportin. As a result, iron accumulates in various organs including the liver, which is severely injured and causes the clinically important hemochromatosis. This diagnosis is difficult to establish due to uncharacteristic features. Among these are asthenia, joint pain, arthritis, chondrocalcinosis, diabetes mellitus, hypopituitarism, hypogonadotropic hypogonadism, and cardiopathy. Diagnosis is initially suspected by increased serum levels of ferritin, a non-specific parameter also elevated in inflammatory diseases that must be excluded to be on the safer diagnostic side. Diagnosis is facilitated if ferritin is combined with elevated fasting transferrin saturation, genetic testing, and family screening. Various diagnostic attempts were published as algorithms. However, none of these were based on evidence or quantitative results derived from scored key features as opposed to other known complex diseases. Among these are autoimmune hepatitis (AIH) or drug-induced liver injury (DILI). For both diseases, the scored diagnostic algorithms are used in line with artificial intelligence (AI) principles to ascertain the diagnosis. The first-line therapy of hemochromatosis involves regular and life-long phlebotomy to remove iron from the blood, which improves the prognosis and may prevent the development of end-stage liver disease such as cirrhosis and hepatocellular carcinoma. Liver transplantation is rarely performed, confined to acute liver failure. In conclusion, ferroptosis, ROS, the gut microbiome, and concomitant alcohol abuse play a major contributing role in the development and clinical course of genetic hemochromatosis, which requires early diagnosis and therapy initiation through phlebotomy as a first-line treatment.<\/jats:p>","DOI":"10.3390\/ijms25052668","type":"journal-article","created":{"date-parts":[[2024,2,26]],"date-time":"2024-02-26T06:50:23Z","timestamp":1708930223000},"page":"2668","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Hemochromatosis: Ferroptosis, ROS, Gut Microbiome, and Clinical Challenges with Alcohol as Confounding Variable"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8910-1200","authenticated-orcid":false,"given":"Rolf","family":"Teschke","sequence":"first","affiliation":[{"name":"Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, D-63450 Hanau, Germany"},{"name":"Academic Teaching Hospital of the Medical Faculty, Goethe University Frankfurt\/Main, D-60590 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.bbagen.2011.08.002","article-title":"The long history of iron in the Universe and in health and disease","volume":"1820","author":"Sheftel","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1063\/PT.3.3815","article-title":"The formation of the heaviest elements","volume":"71","author":"Frebel","year":"2018","journal-title":"Phys. Today"},{"key":"ref_3","unstructured":"Clery, D. (2023, November 19). Some of the Universe\u2019s Heavier Elements Are Created by Neutron Star Collisions. Available online: https:\/\/e.org\/content\/article\/some-universe-s-heavier-elements-are-created-neutron-star-collisions."},{"key":"ref_4","unstructured":"Belford, R. (2023, November 19). The Origin of the Elements. Available online: https:\/\/chem.libretexts.org\/Courses\/University_of_Arkansas_Little_Rock\/Chem_1403%3A_General_Chemistry_2\/Text\/21%3A_Nuclear_Chemistry\/21.06%3A_The_Origin_of_the_Elements."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Teschke, R., and Xuan, T.D. (2022). Heavy metals, halogenated hydrocarbons, phthalates, glyphosate, cordycepin, alcohol, drugs, and herbs, assessed for liver injury and mechanistic steps. Front. Biosci. Landmark, 27.","DOI":"10.31083\/j.fbl2711314"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Teschke, R. (2022). Aluminum, Arsenic, Beryllium, Cadmium, Chromium, Cobalt, Copper, Iron, Lead, Mercury, Molybdenum, Nickel, Platinum, Thallium, Titanium, Vanadium, and Zinc: Molecular aspects in experimental liver injury. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232012213"},{"key":"ref_7","unstructured":"Teschke, R. (Compr. Toxicol, 2024). Hepatotoxicity of copper, iron, cadmium, and arsenic: All formed in the universe from helium and hydrogen via nuclear fusion in stars before arriving at earth and humans, Compr. Toxicol, in press."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"S61","DOI":"10.21037\/atm.2019.01.20","article-title":"Clinical features of Wilson disease","volume":"7","author":"Stremmel","year":"2019","journal-title":"Ann. Transl. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"720","DOI":"10.7326\/0003-4819-115-9-720","article-title":"Wilson disease: Clinical presentation, treatment, and survival","volume":"115","author":"Stremmel","year":"1991","journal-title":"Ann. Intern. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1111\/j.1749-6632.1988.tb55510.x","article-title":"Survival and causes of death in hemochromatosis. Observations in 163 patients","volume":"526","author":"Strohmeyer","year":"1988","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.1056\/NEJM198511143132004","article-title":"Survival and causes of death in cirrhotic and in noncirrhotic patients with primary hemochromatosis","volume":"313","author":"Niederau","year":"1985","journal-title":"N. Engl. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1007\/978-1-4615-2554-7_31","article-title":"Epidemiology, clinical spectrum and prognosis of hemochromatosis","volume":"356","author":"Niederau","year":"1994","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1053\/gast.1996.v110.pm8613000","article-title":"Long-term survival in patients with hereditary hemochromatosis","volume":"110","author":"Niederau","year":"1996","journal-title":"Gastroenterology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1016\/j.tips.2021.05.001","article-title":"Iron metabolism: Pathophysiology and pharmacology","volume":"42","author":"Roemhild","year":"2021","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Vogt, A.C.S., Arsiwala, T., Mohsen, M., Vogel, M., Manolova, V., and Bachmann, M.F. (2021). On iron metabolism and its regulation. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22094591"},{"key":"ref_16","first-page":"164","article-title":"Review on iron and its importance for human health","volume":"19","author":"Abbaspour","year":"2014","journal-title":"J. Res. Med. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1039\/C7MT00136C","article-title":"Iron homeostasis in plants-a brief overview","volume":"9","author":"Connorton","year":"2017","journal-title":"Metallomics"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1016\/j.toxrep.2023.05.010","article-title":"Hepatocyte-specific damage in acute toxicity of sodium ferrous citrate: Presentation of a human autopsy case and experimental results in mice","volume":"10","author":"Nishikawa","year":"2023","journal-title":"Toxicol. Rep."},{"key":"ref_19","unstructured":"Yuen, H.W., and Becker, W. (2023, November 19). Iron Toxicity, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK459224\/."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1002\/cld.1051","article-title":"Pathology of hepatic iron overload","volume":"17","author":"Salomao","year":"2021","journal-title":"Clin. Liver Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1097\/BS9.0000000000000151","article-title":"The evolution of iron-related comorbidities and hospitalization in patients with hemochromatosis: An analysis of the nationwide inpatient sample","volume":"5","author":"MacDougall","year":"2023","journal-title":"Blood Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1182\/asheducation-2009.1.207","article-title":"Molecular mechanisms of normal iron homeostasis","volume":"2009","author":"Zhang","year":"2009","journal-title":"Hematol. Am. Soc. Hematol. Educ. Program."},{"key":"ref_23","unstructured":"Ems, T., St Lucia, K., and Huecker, M.R. (2023, November 19). Biochemistry, Iron Absorption, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK448204\/."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2145","DOI":"10.1172\/JCI114953","article-title":"Iron uptake by human upper small intestine microvillous membrane vesicles. Indication for a facilitated transport mechanism mediated by a membrane iron-binding protein","volume":"86","author":"Teichmann","year":"1990","journal-title":"J. Clin. Investig."},{"key":"ref_25","first-page":"390","article-title":"Regulation of intestinal iron absorption and mucosal iron kinetics in hereditary hemochromatosis","volume":"117","author":"McLaren","year":"1991","journal-title":"J. Lab. Clin. Med."},{"key":"ref_26","first-page":"A1602","article-title":"Iron uptake by rat duodenal microvillous membrane vesicles","volume":"88","author":"Stremmel","year":"1985","journal-title":"Gastroenterology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1111\/j.1365-2362.1987.tb02393.x","article-title":"Iron uptake by rat duodenal microvillous membrane vesicles: Evidence for a carrier-mediated process","volume":"17","author":"Stremmel","year":"1987","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.freeradbiomed.2018.07.020","article-title":"DMT1 and iron transport","volume":"133","author":"Yanatori","year":"2019","journal-title":"Free Radic. Biol. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4716","DOI":"10.3748\/wjg.v13.i35.4716","article-title":"Molecular mechanisms involved in intestinal iron absorption","volume":"13","author":"Sharp","year":"2007","journal-title":"World J. Gastroenterol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1182\/asheducation-2009.1.195","article-title":"Hereditary hemochromatosis: Insights from the Hemochromatosis and Iron Overload Screening (HEIRS) Study","volume":"2009","author":"McLaren","year":"2009","journal-title":"Hematol. Am. Soc. Hematol. Educ. Program."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.gene.2015.10.009","article-title":"HFE gene: Structure, function, mutations, and associated iron abnormalities","volume":"574","author":"Barton","year":"2015","journal-title":"Gene"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1159\/000511551","article-title":"Cytokine and gene expression profiling in patients with HFE-associated hereditary hemochromatosis according to genetic profile","volume":"144","author":"Christoffersen","year":"2021","journal-title":"Acta Haematol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.htct.2021.06.020","article-title":"HFE hemochromatosis: An overview about therapeutic recommendations","volume":"44","author":"Cancado","year":"2022","journal-title":"Hematol. Transfus. Cell Ther."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3018","DOI":"10.1182\/blood.2021011338","article-title":"Hemochromatosis classification: Update and recommendations by the BIOIRON Society","volume":"139","author":"Girelli","year":"2022","journal-title":"Blood"},{"key":"ref_35","unstructured":"Porter, J.L., and Rawla, P. (2023, November 19). Hemochromatosis, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK430862\/."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"66","DOI":"10.14740\/gr1366","article-title":"Managing genetic hemochromatosis: An overview of dietary measures, which may reduce intestinal iron absorption in persons with iron overload","volume":"14","author":"Milman","year":"2021","journal-title":"Gastroenterol. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"18016","DOI":"10.1038\/nrdp.2018.16","article-title":"Haemochromatosis","volume":"4","author":"Brissot","year":"2018","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1089\/109065701753145583","article-title":"Genetic hemochromatosis, a Celtic disease: Is it now time for population screening?","volume":"5","author":"Byrnes","year":"2001","journal-title":"Genet. Test."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1089\/10906570050114876","article-title":"Celtic origin of the C282Y mutation of hemochromatosis","volume":"4","author":"Lucotte","year":"2000","journal-title":"Genet. Test."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1007\/s00439-004-1152-4","article-title":"The origin and spread of the HFE-C282Y haemochromatosis mutation","volume":"115","author":"Distante","year":"2004","journal-title":"Hum. Genet."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"233","DOI":"10.4997\/jrcpe.2018.307","article-title":"Haemochromatosis arthropathy-a conundrum of the Celtic curse","volume":"48","author":"Kiely","year":"2018","journal-title":"J. R. Coll. Physicians Edinb."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1006\/bcmd.2001.0417","article-title":"Frequency analysis and allele map in favor of the celtic origin of the C282Y mutation of hemochromatosis","volume":"27","author":"Lucotte","year":"2001","journal-title":"Blood Cells Mol. Dis."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/S1079-9796(03)00133-5","article-title":"A European allele map of the C282Y mutation of hemochromatosis: Celtic versus Viking origin of the mutation?","volume":"31","author":"Lucotte","year":"2003","journal-title":"Blood Cells Mol. Dis."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1056\/NEJM199909023411002","article-title":"A population-based study of the clinical expression of the hemochromatosis gene","volume":"3411","author":"Olynyk","year":"1999","journal-title":"N. Engl. J. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1038\/ng0896-399","article-title":"A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis","volume":"13","author":"Feder","year":"1996","journal-title":"Nat. Genet."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1016\/j.hoc.2014.04.006","article-title":"Diagnostic evaluation of hereditary hemochromatosis (HFE and non-HFE)","volume":"28","author":"Brissot","year":"2014","journal-title":"Hematol. Oncol. Clin. N. A."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.critrevonc.2015.02.006","article-title":"Update on iron metabolism and molecular perspective of common genetic and acquired disorder, hemochromatosis","volume":"95","author":"Yun","year":"2015","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1002\/mgg3.136","article-title":"Functional consequences of transferrin receptor-2 mutations causing hereditary hemochromatosis type 3","volume":"3","author":"Joshi","year":"2015","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"P1811","DOI":"10.1016\/S0140-6736(23)00287-8","article-title":"Haemochromatosis","volume":"401","author":"Adams","year":"2023","journal-title":"Lancet"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"871","DOI":"10.5604\/01.3001.0012.3169","article-title":"Cirrhosis in hemochromatosis: Independent risk factors in 368 HFE p.C282Y homozygotes","volume":"17","author":"Barton","year":"2018","journal-title":"Ann. Hepatol."},{"key":"ref_51","first-page":"31","article-title":"Hereditary hemochromatosis in a Brazilian university hospital in S\u00e3o Paulo State (1990\u20132000)","volume":"4","author":"Martinelli","year":"2005","journal-title":"Genet. Mol. Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/0168-8278(90)90109-5","article-title":"Liver cell damage and lysosomal iron storage in patients with idiopathic hemochromatosis. A light and electron microscopic study","volume":"11","author":"Glaumann","year":"1990","journal-title":"J. Hepatol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1080\/17474124.2018.1496016","article-title":"Hemochromatosis: Pathophysiology, evaluation, and management of hepatic iron overload with a focus on MRI","volume":"12","author":"Golfeyz","year":"2018","journal-title":"Expert Rev. Gastroenterol. Hepatol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1634S","DOI":"10.3945\/ajcn.117.155960","article-title":"Serum ferritin as an indicator of iron status: What do we need to know?","volume":"106","author":"Daru","year":"2017","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1606S","DOI":"10.3945\/ajcn.117.155887","article-title":"Laboratory methodologies for indicators of iron status: Strengths, limitations, and analytical challenges","volume":"106","author":"Pfeiffer","year":"2017","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Kotla, N.K., Dutta, P., Parimi, S., and Das, N.K. (2022). The role of ferritin in health and disease: Recent advances and understandings. Metabolites, 12.","DOI":"10.3390\/metabo12070609"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"383S","DOI":"10.3945\/ajcn.116.142307","article-title":"Adjusting total body iron for inflammation: Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project","volume":"106","author":"Mei","year":"2017","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"h3692","DOI":"10.1136\/bmj.h3692","article-title":"Interpreting raised serum ferritin levels","volume":"351","author":"Koperdanova","year":"2015","journal-title":"BMJ"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Sandnes, M., Ulvik, R.J., Vorland, M., and Reikvam, H. (2021). Hyperferritinemia-a clinical overview. J. Clin. Med., 10.","DOI":"10.3390\/jcm10092008"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"mfab030","DOI":"10.1093\/mtomcs\/mfab030","article-title":"Optimal serum ferritin level range: Iron status measure and inflammatory biomarker","volume":"13","author":"DePalma","year":"2021","journal-title":"Metallomics"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1016\/j.ajpath.2022.08.010","article-title":"Liver iron loading in alcohol-associated liver disease","volume":"193","author":"Ali","year":"2023","journal-title":"Am. J. Pathol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1007\/s00018-022-04239-9","article-title":"Iron overload in alcoholic liver disease: Underlying mechanisms, detrimental effects, and potential therapeutic targets","volume":"79","author":"Li","year":"2022","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1038\/nrgastro.2015.35","article-title":"Alcoholic liver disease: Mechanisms of injury and targeted treatment","volume":"12","author":"Louvet","year":"2015","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"EASL (2022). EASL clinical practice guidelines on haemochromatosis. J. Hepatol., 77, 479\u2013502.","DOI":"10.1016\/j.jhep.2022.03.033"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"4888","DOI":"10.1002\/jcp.30247","article-title":"Erythroferrone structure, function, and physiology: Iron homeostasis and beyond","volume":"236","author":"Srole","year":"2021","journal-title":"J. Cell. Physiol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1002\/hep.24330","article-title":"Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases","volume":"54","author":"Bacon","year":"2011","journal-title":"Hepatology"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1155\/2006\/934098","article-title":"A diagnostic approach to hemochromatosis","volume":"20","author":"Tavill","year":"2006","journal-title":"Can. J. Gastroenterol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1093\/clinchem\/47.7.1147","article-title":"Hereditary hemochromatosis since discovery of the HFE gene","volume":"47","author":"Lyon","year":"2001","journal-title":"Clin. Chem."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"331","DOI":"10.3399\/bjgp13X668410","article-title":"Diagnosis and management of hereditary haemochromatosis","volume":"63","author":"Sood","year":"2013","journal-title":"Br. J. Gen. Pract."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2230","DOI":"10.1007\/s11606-018-4669-2","article-title":"Diagnosis and management of genetic iron overload disorders","volume":"33","author":"Palmer","year":"2018","journal-title":"J. Gen. Intern. Med."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Dani\u0142owicz-Szymanowicz, L., \u015awi\u0105tczak, M., Sikorska, K., Starzy\u0144ski, R.R., Raczak, A., and Lipi\u0144ski, P. (2021). Pathogenesis, diagnosis, and clinical implications of hereditary hemochromatosis-The cardiological point of view. Diagnostics, 11.","DOI":"10.3390\/diagnostics11071279"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1111\/ijlh.12347","article-title":"Epidemiology and diagnostic testing for hemochromatosis and iron overload","volume":"37","author":"Adams","year":"2015","journal-title":"Int. J. Lab. Hematol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1002\/hep.22322","article-title":"Simplified criteria for the diagnosis of autoimmune hepatitis","volume":"48","author":"Hennes","year":"2008","journal-title":"Hepatology"},{"key":"ref_74","first-page":"4","article-title":"DILI, HILI, RUCAM algorithm, and AI, the Artificial Intelligence: Provocative issues, progress, and proposals","volume":"1","author":"Teschke","year":"2020","journal-title":"Arch. Gastroenterol. Res."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Teschke, R., and Danan, G. (2021). Idiosyncratic drug-induced liver injury (DILI) and herb-induced liver injury (HILI): Diagnostic algorithm based on the quantitative Roussel Uclaf Causality Assessment Method (RUCAM). Diagnostics, 11.","DOI":"10.3390\/diagnostics11030458"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1016\/0895-4356(93)90101-6","article-title":"Causality assessment of adverse reactions to drugs\u2013I. A novel method based on the conclusions of international consensus meetings: Application to drug-induced liver injuries","volume":"46","author":"Danan","year":"1993","journal-title":"J. Clin. Epidemiol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1016\/0895-4356(93)90102-7","article-title":"Causality assessment of adverse reactions of drugs\u2013II. An original model for validation of drug causality assessment methods: Case reports with positive rechallenge","volume":"46","author":"Danan","year":"1993","journal-title":"J. Clin. Epidemiol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"853","DOI":"10.3389\/fphar.2019.00853","article-title":"Roussel Uclaf Causality Assessment Method for drug-induced liver injury: Present and future","volume":"10","author":"Danan","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Danan, G., and Teschke, R. (2016). RUCAM in drug and herb induced liver injury: The update. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17010014"},{"key":"ref_80","unstructured":"European Commission (2023, December 17). White Paper on Artificial Intelligence\u2013A European Approach to Excellence and Trust, Released 19 February 2020. Available online: https:\/\/ec.europa.eu\/info\/sites\/info\/files\/commission-white-paper-artificial-intelligence-feb2020_en.pdf."},{"key":"ref_81","unstructured":"McCarthy, J., Minsky, M.L., Rochester, N., and Shannon, C.E. (2023, December 17). A Proposal for the Dartmouth Summer Research Project on Artificial Intelligence. Available online: http:\/\/www-formal.stanford.edu\/jmc\/history\/dartmouth\/dartmouth.html."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"47","DOI":"10.2478\/v10136-012-0031-x","article-title":"Artificial neural networks in medical diagnosis","volume":"11","author":"Amato","year":"2013","journal-title":"J. Appl. Biomed."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"100154","DOI":"10.1016\/j.jhepr.2020.100154","article-title":"Systemic iron reduction by venesection alters the gut microbiome in patients with haemochromatosis","volume":"2","author":"Parmanand","year":"2020","journal-title":"JHEP Rep."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1111\/trf.13328","article-title":"Erythrocytapheresis versus phlebotomy in the maintenance treatment of HFE hemochromatosis patients: Results from a randomized crossover trial","volume":"56","author":"Winkens","year":"2016","journal-title":"Transfusion"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1111\/ejh.12530","article-title":"Deferasirox in patients with iron overload secondary to hereditary hemochromatosis: Results of a 1-yr Phase 2 study","volume":"95","author":"Melo","year":"2015","journal-title":"Eur. J. Haematol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1671","DOI":"10.1002\/hep.23879","article-title":"A phase 1\/2 dose-escalation trial of deferasirox for the treatment of iron overload in HFE-related hereditary hemochromatosis","volume":"52","author":"Phatak","year":"2010","journal-title":"Hepatology"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"143","DOI":"10.2991\/chi.k.200726.001","article-title":"What\u2019s important and new in hemochromatosis?","volume":"2","author":"Brissot","year":"2020","journal-title":"Clin. Hematol. Int."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1002\/lt.26539","article-title":"Long-term outcomes and trends in liver transplantation for hereditary hemochromatosis in the United States","volume":"29","author":"Lymberopoulos","year":"2023","journal-title":"Liver Transpl."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1002\/hep.510310227","article-title":"Iron overload in cirrhosis-HFE genotypes and outcome after liver transplantation","volume":"31","author":"Brandhagen","year":"2000","journal-title":"Hepatology"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1002\/lt.500050503","article-title":"Long-term follow-up after liver transplantation in patients with hepatic iron overload","volume":"5","author":"Tung","year":"1999","journal-title":"Liver Transpl. Surg."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"e560","DOI":"10.1097\/TXD.0000000000001007","article-title":"Long-term outcome of orthotopic liver transplantation in patients with hemochromatosis: A summary of a 30-year transplant program","volume":"6","author":"Dobrindt","year":"2020","journal-title":"Transpl. Direct"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1002\/hep.26570","article-title":"Liver transplantation normalizes serum hepcidin level and cures iron metabolism alterations in HFE hemochromatosis","volume":"59","author":"Philip","year":"2014","journal-title":"Hepatology"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1055\/s-0031-1286059","article-title":"The molecular pathogenesis of hereditary hemochromatosis","volume":"31","author":"Babitt","year":"2011","journal-title":"Semin. Liver Dis."},{"key":"ref_94","unstructured":"Faruqi, A., and Mukkamalla, S.K.R. (2023). Iron Binding Capacity, StatPearls Publishing. Updated 2 January 2023."},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Yilmaz, B., and Li, H. (2018). Gut microbiota and iron: The crucial factors in health and disease. Pharmaceuticals, 11.","DOI":"10.3390\/ph11040098"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"103","DOI":"10.3389\/fnut.2018.00103","article-title":"Inherited disorders of iron overload","volume":"5","author":"Pantopoulos","year":"2018","journal-title":"Front. Nutr."},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Schmidtke, J. (2022). Twenty-Five years of contemplating genotype-based hereditary hemochromatosis population screening. Genes, 13.","DOI":"10.3390\/genes13091622"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"360438","DOI":"10.1155\/2014\/360438","article-title":"Lipid peroxidation: Production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal","volume":"2014","author":"Ayala","year":"2014","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"521","DOI":"10.3748\/wjg.v25.i5.521","article-title":"Iron and liver fibrosis: Mechanistic and clinical aspects","volume":"25","author":"Mehta","year":"2019","journal-title":"World J. Gastroenterol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1016\/0378-4274(95)03532-X","article-title":"Toxicity of iron and hydrogen peroxide: The Fenton reaction","volume":"82\u201383","author":"Winterbourn","year":"1995","journal-title":"Toxicol. Lett."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1002\/hep.510260311","article-title":"Excess iron induces hepatic oxidative stress and transforming growth factor beta1 in genetic hemochromatosis","volume":"26","author":"Houglum","year":"1997","journal-title":"Hepatology"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1002\/ajh.20743","article-title":"Oxidative stress in asymptomatic subjects with hereditary hemochromatosis","volume":"82","author":"Shizukuda","year":"2007","journal-title":"Am. J. Hematol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1007\/s12265-016-9704-2","article-title":"Iron overload or oxidative stress? Insight into a mechanism of early cardiac manifestations of asymptomatic hereditary hemochromatosis subjects with C282Y homozygosity","volume":"9","author":"Shizukuda","year":"2016","journal-title":"J. Cardiovasc. Transl. Res."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/S0022-2143(99)90022-7","article-title":"Hepatic lipid peroxidation in hereditary hemochromatosis and alcoholic liver injury","volume":"133","author":"Parkkila","year":"1999","journal-title":"J. Lab. Clin. Med."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"2505","DOI":"10.1016\/S0021-9258(18)63099-6","article-title":"Hepatic microsomal ethanol-oxidizing system. In vitro characteristics and adaptive properties in vivo","volume":"245","author":"Lieber","year":"1970","journal-title":"J. Biol. Chem."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1016\/0006-291X(72)90594-3","article-title":"Microsomal ethanol-oxidizing system (MEOS): Purification and properties of a rat liver system free of catalase and alcohol dehydrogenase","volume":"49","author":"Teschke","year":"1972","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Teschke, R. (2018). Alcoholic liver disease: Alcohol metabolism, cascade of molecular mechanisms, cellular targets, and clinical aspects. Biomedicines, 6.","DOI":"10.3390\/biomedicines6040106"},{"key":"ref_108","doi-asserted-by":"crossref","unstructured":"Teschke, R. (2019). Alcoholic liver disease: Current mechanistic aspects with focus on their clinical relevance. Biomedicines, 7.","DOI":"10.3390\/biomedicines7030068"},{"key":"ref_109","first-page":"9","article-title":"Alcoholic liver disease and the co-triggering role of MEOS with its CYP 2E1 catalytic cycle and ROS","volume":"2","author":"Teschke","year":"2021","journal-title":"Arch. Gastroenterol. Res."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1016\/j.freeradbiomed.2007.11.004","article-title":"CYP2E1 and oxidative liver injury by alcohol","volume":"44","author":"Lu","year":"2008","journal-title":"Free Radic. Biol. Med."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1016\/0891-5849(89)90033-6","article-title":"Oxygen radical generation by microsomes: Role of iron and implications for alcohol metabolism and toxicity","volume":"7","author":"Cederbaum","year":"1989","journal-title":"Free Radic. Biol. Med."},{"key":"ref_112","doi-asserted-by":"crossref","unstructured":"Harjum\u00e4ki, R., Pridgeon, C.S., and Ingelman-Sundberg, M. (2021). CYP2E1 in alcoholic and non-alcoholic liver injury. Roles of ROS, reactive intermediates and lipid overload. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22158221"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1016\/S0168-8278(96)80214-5","article-title":"Hepatotoxicity induced by iron overload and alcohol. Studies on the role of chelatable iron, cytochrome P450 2E1 and lipid peroxidation","volume":"25","author":"Johansson","year":"1996","journal-title":"J. Hepatol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1152\/physrev.1997.77.2.517","article-title":"Cytochrome P-4502E1: Its physiological and pathological role","volume":"77","author":"Lieber","year":"1997","journal-title":"Physiol. Rev."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1159\/000046892","article-title":"Ethanol consumption and liver mitochondria function","volume":"10","author":"Cunningham","year":"2001","journal-title":"Biol. Signals Recept."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"332","DOI":"10.4254\/wjh.v12.i7.332","article-title":"Oxidative stress in alcohol-related liver disease","volume":"12","author":"Tan","year":"2020","journal-title":"World J. Hepatol."},{"key":"ref_117","first-page":"277","article-title":"Alcohol, oxidative stress, and free radical damage","volume":"27","author":"Wu","year":"2003","journal-title":"Alcohol. Res. Health"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"39","DOI":"10.20517\/2394-5079.2018.29","article-title":"Oxidative stress and hepatocarcinogenesis","volume":"4","author":"Fu","year":"2018","journal-title":"Hepatoma Res."},{"key":"ref_119","doi-asserted-by":"crossref","unstructured":"Mac\u00edas-Rodr\u00edguez, R.U., Inzaugarat, M.E., Ruiz-Marg\u00e1in, A., Nelson, L.J., Trautwein, C., and Cubero, F.J. (2020). Reclassifying hepatic cell death during liver damage: Ferroptosis\u2014A novel form of non-apoptotic cell death?. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21051651"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1038\/s41419-020-2732-5","article-title":"The emerging role of ferroptosis in non-cancer liver diseases: Hype or increasing hope?","volume":"11","author":"Mao","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1038\/s41420-021-00660-4","article-title":"Ferroptosis in liver disease: New insights into disease mechanisms","volume":"7","author":"Wu","year":"2021","journal-title":"Cell Death Discov."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/s41419-020-2298-2","article-title":"Ferroptosis: Past, present and future","volume":"11","author":"Li","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"9179","DOI":"10.1002\/jcp.26954","article-title":"Ferritinophagy\/ferroptosis: Iron-related newcomers in human diseases","volume":"233","author":"Tang","year":"2018","journal-title":"J. Cell. Physiol."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1038\/s41420-023-01608-6","article-title":"Ferroptosis contributes to ethanol-induced hepatic cell death via labile iron accumulation and GPx4 inactivation","volume":"9","author":"Luo","year":"2023","journal-title":"Cell Death Discov."},{"key":"ref_125","doi-asserted-by":"crossref","unstructured":"Lawless, M.W., Mankan, A.K., White, M., O\u2019Dwyer, M.J., and Norris, S. (2007). Expression of hereditary hemochromatosis C282Y HFE protein in HEK293 cells activates specific endoplasmic reticulum stress responses. BMC Cell Biol., 8.","DOI":"10.1186\/1471-2121-8-30"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1165\/ajrcmb.23.1.4014","article-title":"Mitogen-activated protein kinases regulate cytokine gene expression in human airway myocytes","volume":"23","author":"Hedges","year":"2000","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"1757","DOI":"10.1084\/jem.188.9.1757","article-title":"Endothelial cell \u201cmemory\u201d of inflammatory stimulation: Human venular endothelial cells store interleukin 8 in Weibel-Palade bodies","volume":"188","author":"Wolff","year":"1998","journal-title":"J. Exp. Med."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"1751","DOI":"10.1084\/jem.188.9.1751","article-title":"Rapid secretion of prestored interleukin 8 from Weibel-Palade bodies of microvascular endothelial cells","volume":"188","author":"Utgaard","year":"1998","journal-title":"J. Exp. Med."},{"key":"ref_129","doi-asserted-by":"crossref","unstructured":"Teng, Y., Gao, L., M\u00e4kitie, A.A., Florek, E., Czarnywojtek, A., Saba, N.F., and Ferlito, A. (2023). Iron, Ferroptosis, and Head and Neck Cancer. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms242015127"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/S0741-8329(03)00128-9","article-title":"Hemochromatosis and alcoholic liver disease","volume":"30","author":"Fletcher","year":"2003","journal-title":"Alcohol"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/5\/2668\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:04:40Z","timestamp":1760105080000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/5\/2668"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,25]]},"references-count":130,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2024,3]]}},"alternative-id":["ijms25052668"],"URL":"https:\/\/doi.org\/10.3390\/ijms25052668","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,25]]}}}