鐵 (1)，它竟是致命的罪魁禍首，每年導致 1100 萬慢性病人的死亡。
金豬寶 （2024年3月13日）
經過長時間的研究，我終於找到了導致慢性病人死亡的真正罪魁禍首。 鐵是造成世界上每年約 1100 萬人死亡的主要原因（並非全部原因）。這個發現讓我自己都震驚了。它與全球每天約 30, 0000 人死亡有關。
《部分摘要》：鐵劑輸注自 19 世紀初以來一直用於治療貧血，並於 50 世紀獲得認可。以後的研究證實，異常的鐵會損害患者的所有細胞、所有器官和所有部位，並加速各種癌症的生長。在大量變量的影響下，異常的鐵以不可預測的方式通過多種機製導致細胞損傷......我將展示為什麽鐵引起的副作用在臨床上經常被忽視，為什麽鐵引起的副作用比想像更普遍、更致命。為什麽鐵引起的副作用被忽視或未被識別或誤認為是感染/藥物的副作用，以及它們如何對患者造成廣泛的、無症狀的、非特異性的（通常像疾病和藥物的作用）、進行性的、常常無法識別、未被充分認識的細胞損傷。我證明鐵毒性是破壞人體健康的主要手段，影響著全球超過 10 億貧血人群……。
鐵是必不可少的。 人沒有鐵就一分鍾無法生存。 鐵就像一個核武器；當被國家當局很好地控製時，沒問題。 然而，當它被壞人控製時，放在京城省會時，那會是什麽結果呢？
當鐵過量或調節不當時，它會損壞細胞中的DNA、蛋白質、脂肪和所有生物材料。 它幹擾所有生物過程、免疫係統等，並且可以加速各種癌症的生長！中風、心髒病、高血壓、各種結石、組織鈣化等等都可追到這個殺手！ 在看到這些引用的研究之前，沒有人會相信這一點。
醫院使用的大多數醫療方法都是基於 1950 或1980 年以前的知識。 這些參考文獻引用的研究大部分是2010年至2023年的。每天的新發現都可能震驚世界，但會被利益集團封鎖。 參考文獻隻是一小部分，因為許多期刊沒有在我檢索的數據庫中建立索引。 想想都覺得可怕。大多數醫生都會犯致命的錯誤：他們會帶著配偶和孩子去醫院治療慢性病，而不知道醫院使用方法存在巨大的知識滯後。
簡而言之，鐵在人體內的代謝和運輸必須嚴格控製和監管，以避免它的致命禍害。 當人出現炎症時，某些炎症細胞因子會導致鐵的代謝和運輸失調，導致鐵在一些重要器官如肝髒、肺等積累。過量的鐵會產生OH-自由基。 OH-自由基的出現會導致更嚴重要器官炎症和全身炎症。加重的炎症會導致更嚴重的鐵的失調，開始惡性循環（更多的鐵，更多OH-自由基，更嚴重的炎症，器官內更多的鐵，更多自由基，更嚴重的炎症， 更大破壞力，永遠持續下去），直到殺死患者。 即使患者血液中缺乏鐵，或患有所謂的缺鐵性貧血（甚至疾病名稱也有誤導性），這種惡性循環情況也可能發生（而且常常發生）。
我的2萬多字文章將會發表。 然而，這篇文章需要很長時間才能發表。 當我想到每天的死亡人數約為30000人時（5400000 半年），我不能沉默。當一個人知道影響這麽多人命的秘密不說，那是太缺德了。
我不能在這裏討論所有的發現，但會在這個係列中討論許多相關的問題。 雖然慢性病的潛在解決方案很複雜並且取決於個體的情況，但目前的治療方法、用鐵劑量等等都是錯誤的。我的研究結論為所有慢性病治療指出了新的方向。我希望這post能給有人們一個提示，使他們能夠避免醫療係統的致命治療方法。 為了顯示證據的強度，我提供了我審閱過的大部分參考文獻。
奇怪的是，每個項發表的研究都隻談自己的結論， 它不提它的結論意味著千百萬人的命！研究者更不會把千萬的研究結論（包括其他的已知的死因）一起考慮，他們沒有膽量說鐵是所有慢性病致命的罪魁禍首 （中風、心髒病、高血壓、結石、組織鈣化等等，看起來不明顯）。我的結論意味著慢性病不治論很快就要徹底倒了。我想以後研究還要探討其他金屬在什麽情況下對慢性病人有相似的效應。
一個很有用的要發明的儀器是測人體鐵分布儀，靠檢查測磁場或鐵元素的共振。 鐵分布圖能確定鐵在不同器官的濃度和危害程度。難處是要達到很高的靈敏度。
參考文獻（在最後）
English version
Iron (1), it is the most deadly weapon affecting 11 millions of chronic disease deaths each year.
From my long study, I finally got the real culprit of deaths. Iron is the killing weapon employed by all chronic diseases and is mainly (not entirely) responsible for about 11 million deaths in the world.
The finding shocks myself. It is mainly responsible for about 30, 0000 deaths each day in the world.
Partial findings: Iron infusion has been used for treatment of anemia since the early 19 century and gained acceptance in the 50th. Subsequent studies have firmly established that aberrant iron can damage all cells, all organs, and all parts in the patient, and accelerate cancer growth for all kinds of cancer. Aberrant iron causes cellular damage by multiple mechanisms in an unpredictable manner under influences of a large number of variables.... I show why iron-induced adverse effects are routinely dismissed in clinic, why they are magnitudes more prevalent and more deadly than what are believed, why they were ignored or unrecognized or mistaken as those of infections/drugs, and how they cause widespread, asymptomatic, nonspecific (often mimic those of diseases and drugs), progressive, often unrecognizable, and under-appreciated cellular damages to the patient. I prove that iron toxicity is the primary arm for ruining host health, affecting more than a billion anemic people globally….
Iron is essential. A person cannot survive for one minute without iron. Iron is like a great nuclear weapon for nation when iron is controlled well by the national authority. However, when it is controlled by a wrong hand, and is placed in the capital city, and province capitals, what would be the outcome? Destruction of the nation!
Iron is just like nuclear weapon: when iron is in excess or under-regulated (uncontrolled), it can damage DNA, protein, fat and all biological materials in cells. It can interfere with all biological processes, the immune system, etc. and it can speed up cancer growth for all kinds of cancer. Stroke, heart disease, high blood pressure, all kinds of stones can be traced this evil killer! No one can believe it before seeing those cited studies.
Most practices used by hospitals are based on knowledge of 1950 for before. Those references cited studies are most from 2010 to 2023. Chances are that new discoveries could shock the world but not suppressed by interest holders. The references are only a small set because many journals are not indexed in the databases I searched. It is scared to think about it.
Most doctors would make deadly mistakes: they will bring their spouses and children to hospitals for treating chronic diseases without knowing the huge knowledge lag.
To state the story in short: Iron must be tightly controlled and regulated to avoid iron’s deadly effects. When a person has inflammation, certain inflammatory cytokines will lead to dis-regulation of iron metabolism and transportation, and will cause iron to be accumulated in some vital organs such as liver, lungs, etc. The excess iron is responsible for generating radicals, which can cause more inflammation in both the vital organs and the whole body. It cause more iron disregulation, starting the vicious circle (more iron, more inflammation, or destructive force, keeping on forever) until the uncontrolled iron kills the patient. This can happen even when the patient lacks iron in blood or suffer so-called iron-deficiency anemia (even the disease name used in medicine is misleading).
The 20,000-words article will be published. However, it would take a long time to have the article published. When I think the death count is about 30,000 a day, I cannot do nothing in the scam medical publication system.
I cannot put massive discoveries here, but I will discuss many related problems in a series. While potential solutions to chronic diseases are complicated and depend on individual conditions, it is wrong to use iron in the current methods, dosages, etc. The findings also point to a new direction for treating chronic diseases. I hope this post will give thinking people a hint so that they can avoid the deadly consequences in the health care system. To show the strength of evidence, I provide most references I have reviewed.
What is strange is that each published study only talks about its own conclusions. It does not mention that its conclusions mean millions of lives! Researchers will not consider the conclusions of tens of millions of studies (including those about other known causes of death) together. They have no guts to say that iron is primarily responsible for deaths in all chronic diseases (the roles of iron in stroke, heart disease, high blood pressure, stones, tissue calcification, etc. are not obvious). My conclusion means that incurable notion of chronic diseases will soon completely repudiated. I think future research will also explore under what circumstances other metals have similar effects on chronic disease patients.
A very useful instrument to be invented is a human iron distribution machine, which detects magnetic fields or resonances of iron elements. An iron mapping can determine iron local concentrations and degrees of harm of iron in different organs. One obvious difficulty is how to achieve very high sensitivity.
[end]
參考文獻（References）
1. Blaud P. [Sur les maladies chloropiques et sur un mode de traitement specifique dons ces affecions (]. Rev Med Fr Etrang. 1832; 45: 357-67 French)
2. Baird IM, Podmore DA, Intramuscular iron therapy in iron-deficiency anaemia. Lancet, 1954
3. Cançado RD, Muñoz M. Intravenous iron therapy: how far have we come? Rev Bras Hematol Hemoter. 2011;33(6):461-9. doi: 10.5581/1516-8484.20110123;
4. Auerbach M, Ballard H. (2010). Clinical Use of Intravenous Iron: Administration, Efficacy, and Safety,’ ASH Education Book, vol. 2010, pp. 338-347.
5. de Las Cuevas Allende R, Díaz de Entresotos L, Conde Díez S. Anaemia of chronic diseases: Pathophysiology, diagnosis and treatment. Med Clin (Barc). 2021 Mar 12;156(5):235-242. doi: 10.1016/j.medcli.2020.07.035.
5b. Ponka P. Beaumont C. Richardson DR. Function and regulation of transferrin and ferritin. Semin Hematol.1998;35:35–54.
6. Nemeth E, Ganz T. 2014. Anemia of inflammation. Hematol. Oncol. Clin. N. Am. 28:671–81
7. Torti SV, Manz DH, Paul BT, et al. Iron and Cancer. Annu Rev Nutr. 2018 August 21; 38: 97–125. doi:10.1146/annurev-nutr-082117-051732.
8. Chen Y, Fan Z, Yang Y, Gu C. Iron metabolism and its contribution to cancer (Review). Iron metabolism and its contribution to cancer (Review). Int J Oncol 2019; 54 (4):1143-1154. https://doi.org/10.3892/ijo.2019.4720
9. Tatiane V, Velmurugan N, Smith C, et al. Osteomalacia as a Complication of Intravenous Iron Infusion: A Systematic Review of Case Reports Journal of Bone and Mineral Research. 2022;37(6)1188-1199. https://doi.org/10.1002/jbmr.4558.
10. Schaefer B, Tobiasch M, Viveiros A, et al. Hypophosphataemia after treatment of iron deficiency with intravenous ferric carboxymaltose or iron isomaltoside—a systematic review and meta-analysis. Br J Clin Pharmacol. 2021;87:2256–2273. https://doi.org/10.1111/bcp.14643 (FCM is associated with a high risk of hypophosphataemia, which does not resolve for at least 3 months in a large proportion of affected patients.)
11. Vecchio LD, Ekart, Ferro CJ, et al. Intravenous iron therapy and the cardiovascular system: risks and benefits. Clinical Kidney Journal, April 2021; 14(4):1067–1076, https://doi.org/10.1093/ckj/sfaa212 (IV iron therapy has been associated with increased risks of atherothrombosis, vascular calcification, oxidative stress and infection, leading to the fear that excessive IV iron therapy could be associated with worse outcomes.”).
12. Szebeni J, Fishbane S, Hedenus M, et al. Hypersensitivity to intravenous iron: classification, terminology, mechanisms and management. Br J Pharmacol. 2015; 172(21): 5025–36. https://doi.org/10.1111/bph.13268.)
13. Abe C, Miyazawa T, Miyazawa T. Current Use of Fenton Reaction in Drugs and Food. Molecules. 2022 Sep;27(17):5451. doi: 10.3390/molecules27175451
14. Alfadda AA, Sallam RM. Reactive Oxygen Species in Health and Disease. BioMed Research International. 2012;936486. https://doi.org/10.1155/2012/936486
15. Liang W, Ferrara N. Iron Metabolism in the Tumor Microenvironment: Contributions of Innate Immune Cells. Front Immunol. 2020;11: 626812. doi: 10.3389/fimmu.2020.626812
16. Cohen A, Chackocorresponding B. Severe hypocalcaemia following denosumab and iron infusion. Nephrology (Carlton). 2022 Sep; 27(9):781–782. doi: 10.1111/nep.14078 (Hypophosphataemia occurs 1 and 2 weeks after intravenous iron and can persist for to 6–12 weeks. Reductions in serum calcium occur up to 6 months after denosumab.)
17. Pinarba?li A, Tunca O, Kazan S, Dizen K. The Effect of Intravenous Iron Replacement Therapy on Calcium, Phosphorus, and Parathormone Levels in Advanced-Stage Chronic Kidney Disease. JOJ uro. & nephron. 2023;8(1): JOJUN.MS.ID.555728. DOI: 10.19080/JOJUN.2023.08.555728.
18. Sullivan A, LanhamT, Rubin A. A rare case of parental iron-induced persistent hypophosphatemia. Journal of Community Hospital Internal Medicine Perspectives, 2020;10:2,166-167, DOI: 10.1080/20009666.2020.1746521
19. Glaspy JA, Wolf M, Strauss WE. Intravenous Iron-Induced Hypophosphatemia: An Emerging Syndrome. Review Adv Ther. 2021 Jul;38(7):3531-3549. doi: 10.1007/s12325-021-01770-2.
20. Vasquez-Riosa G, Chapela A, Philipb I, et al. Life-threatening hypophosphatemia following intravenous iron infusion. Nefrología. 2021;41(4):367-488. DOI: 10.1016/j.nefroe.2021.08.006.
21. Zoller H, Wolf M, Blumenstein I, et al. Hypophosphataemia following ferric derisomaltose and ferric carboxymaltose in patients with iron deficiency anaemia due to inflammatory bowel disease (PHOSPHARE-IBD): a randomised clinical trial. Gut 2023;72:644–653. doi:10.1136/gutjnl-2022-327897.
22. Anand G, Schmid C. Severe hypophosphataemia after intravenous iron administration. BMJ Case Rep 2017. doi:10.1136/bcr-2016-219160. (We stress the need of increased awareness of this potential complication among physicians. Patients should be informed of this complication and instructed to report for follow-up if they experience new musculoskeletal symptoms or worsening of tiredness.)
23. Wong KY, Yu KY, Mak M.WH, et al. Intravenous iron isomaltoside (Monofer)–induced hypophosphataemia: a case report. Hong Kong Med J. 2022 Jun;28(3):267–9. https://doi.org/10.12809/hkmj219354
24. Hardy S, Vandemergel X. Intravenous Iron Administration and Hypophosphatemia in Clinical Practice. International Journal of Rheumatology, vol. 2015, Article ID 468675, 6 pages, 2015. https://doi.org/10.1155/2015/468675 (Hypophosphatemia is frequent after parenteral FCM injection and may have clinical consequences, including persistent fatigue.*)
25. Kim J and Wessling-Resnick M. The Role of Iron Metabolism in Lung Inflammation and Injury. J Allergy Ther. 2012;3(Suppl 4): doi:10.4172/2155-6121.S4-004. (Lungs are the most vulnerable organ for ion-damages. Moreover, based on radioisotope-labeled study, injected iron is largely in lung tissues (54%) with remaining metal associated with bronchoalveolar lavage protein as bound (22%) and unbound (5%) forms and lung transferrin concentrations are regulated by local synthesis in a manner independent of body iron status. Among many organs in the body, the lungs may have the greatest susceptibility to metal-induced oxidative stress due to its unique anatomical role for massive oxygen exchange along with large blood supplies.
26. Heilig EA, Thompson KJ, Molina RM, et al. Manganese and iron transport across pulmonary epithelium. Am J Physiol Lung Cell Mol Physiol. 2006; 290:L1247-1259.) (All of those studies imply the respiratory system is the most vulnerable to excessive iron.)
27. Emerit J, Beaumont C, Trivin F. Iron metabolism, free radicals, and oxidative injury. Biomed Pharmacother. 2001 Jul;55(6):333-9. doi: 10.1016/s0753-3322(01)00068-3. (Excessive iron buildup in the lungs could be a major cause of chronic obstructive pulmonary disease. The stress caused by excessive iron buildup in mitochondria can lead to inflammation and damage to the lung's air sacs and cells that line the airways. This kind of damages to lungs by free radicals and oxidative stress took a few days to show up. The excess mitochondrial iron in lungs may generate hydroxyl radicals that promote inflammation, cell death and oxidative stress.
28. Zhang V, Ganz T, Nemeth E, Kim A. Iron overload causes a mild and transient increase in acute lung injury. Physiol Rep. 2020 Jun;8(12):e14470. Published online 2020 Jun 29. doi: 10.14814/phy2.14470.
29. Cloonan SM, Glass K, Laucho-Contreras ME, et al. Mitochondrial iron chelation ameliorates cigarette smoke-induced bronchitis and emphysema in mice. Nature Medicine. 2016:22,163-174. (It has been found that deferiprone (DFP), an orally administered drug was able to prevent and even reverse the lung inflammation.)
30. Ahluwalia MS, Patel S, Daw H. Myocardial Infarction Induced by Intravenous Iron Dextran Infusion in Absence of Coronary Artery Disease. Blood. 2004;104 (11):3694. https://doi.org/10.1182/blood.V104.11.3694.3694. (Immediately after the infusion the patient developed anaphylactic type reaction and complained of severe chest pain and shortness of breath);
31. Sawicki KT, Ardehali H. Intravenous Iron Therapy in Heart Failure With Reduced Ejection Fraction: Tackling the Deficiency/ Circulation. 2021;144:253–255. (Excess iron is cardiotoxic and overtreatment of patients with HFrEF with intravenous iron may have detrimental effects. Important questions remain about the effect of intravenous iron on myocardial and endothelial function, mortality, and long-term safety, especially in the setting of infection and inflammation.).
32. Naito Y, Tsujino T, Masuyama T, Ishihara M. Crosstalk between Iron and Arteriosclerosis. J Atheroscler Thromb. 2022 Mar 1; 29(3): 308–314. doi: 10.5551/jat.RV17060 (Iron is considered to be involved in the pathogenesis of arteriosclerosis and in fact, clinical and experimental studies have shown an association between iron and arteriosclerosis.).
33. Sharkey-Toppen TP, Tewari AK, Raman SV. Iron and Atherosclerosis: Nailing Down a Novel Target with Magnetic Resonance. J Cardiovasc Transl Res. 2014 Jul; 7(5): 533–542. doi: 10.1007/s12265-014-9551-y.
34. Reis KA, Guz G, Ozdemir H, et al. Intravenous iron therapy as a possible risk factor for atherosclerosis in end-stage renal disease. Int Heart J. 2005 Mar;46(2):255-64. doi: 10.1536/ihj.46.255.
35. Savarese G, von Haehling S, Butler J, et al. Iron deficiency and cardiovascular disease. European Heart Journal, January 2023;44(1):14–27. https://doi.org/10.1093/eurheartj/ehac569 (Iron deficiency (ID) is common in patients with cardiovascular disease. Up to 60% of patients with coronary artery disease, and an even higher proportion of those with heart failure (HF) or pulmonary hypertension have ID;)
36. Vecchio LD, see 11*
37. Lee T-S, Shiao M-S, Pan C-C, Chau L-Y. Iron-Deficient Diet Reduces Atherosclerotic Lesions in ApoE-Deficient Mice. Circulation. 1999;99:1222–1229 https://doi.org/10.1161/01.CIR.99.9.1222
38. Li J-D, Guo L, Guo S-S, et al. Hemochromatosis resulted from large-dose intravenous iron injection in hemodialysis patients: a report of two cases. Int J Clin Exp Med 2018;11(4):4211-4214. (Iron infusion can cause damage to vital organs (liver and spleen) and destroy platelets. This case report two cases of hemochromatosis that resulted from a large dose of intravenous iron injection in hemodialysis patients. Clinical manifestations included liver enlargement, liver fibrosis or even cirrhosis, splenomegaly and other solid organ dysfunctions. Case one manifested as liver cirrhosis and case two manifested as confusion in consciousness. These two cases both manifested as thrombocytopenia, and increased density of the liver and spleen. Eventually both patients died a few days later.)
39. Price L, Kowdley KV. The role of iron in the pathophysiology and treatment of chronic hepatitis C. Can J Gastroenterol. 2009;23(12):822-828.
40. Pietrangelo A. Iron and the liver. Liver Int. 2016; 36(Suppl 1):116–123.
41. Ko C, Siddaiah N, Berger J, et al. Prevalence of hepatic iron overload and association with hepatocellular cancer in end-stage liver disease: results from the National Hemochromatosis Transplant Registry. Liver Int. 2007;27(10):1394-1401.
42. Kowdley KV. Iron Overload in Patients With Chronic Liver Disease. Gastroenterology & Hepatology. November 2016;12(11):695-698
43. Akatsu H, Manabe T, Kawade Y. Iron deposition in autopsied liver specimens from older patients receiving intravenous iron infusion. PLoS ONE 15(8): e0237104. https://doi.org/10.1371/journal.pone.0237104
44. Elmberg M, Hultcrantz R, Ekbom A, Brandt L, Olsson S, et al. 2003. Cancer risk in patients with hereditary hemochromatosis and in their first-degree relatives. Gastroenterology 125:1733–41 (20-200 folds of liver cancer?).
45 Kowdley KV, Belt P, Wilson LA, et al. Serum ferritin is an independent predictor of histologic severity and advanced fibrosis in patients with nonalcoholic fatty liver disease. Hepatology. 2012;55(1):77-85.
46. Agarwal R, Rizkala AR, Kaskas MO, et al. Iron sucrose causes greater proteinuria than ferric gluconate in non-dialysis chronic kidney disease. Kidney Int. 2007;72:638–642. https://doi.org/10.1038/sj.ki.5002422.
47. Bishu K, Agarwal R. Acute injury with intravenous iron and concerns regarding long-term safety. DOI: 10.2215/CJN.01420406
48. Kang H-T, Linton JA, Kwon SK, et al. Ferritin Level Is Positively Associated with Chronic Kidney Disease in Korean Men, Based on the 2010–2012 Korean National Health and Nutrition Examination Survey. Int J Environ Res Public Health. 2016; 13(11): 1058. doi: 10.3390/ijerph13111058
49. Martines AM, Masereeuw R, Tjalsma H. Iron metabolism in the pathogenesis of iron‐induced kidney injury. Nat Rev Nephrol 2013;9:385‐398.
50. Baliga R, Ueda N, Shah SV. Increase in bleomycin-detectable iron in ischaemia/reperfusion injury to rat kidneys. Biochem J. 1993; 291(Pt 3):901–905.
51. Kassianides X, Hazara AM, Bhandari S. Improving the safety of intravenous iron treatments for patients with chronic kidney disease. Expert Opin Drug Saf. 2021;20:23–35. doi: 10.1080/14740338.2021.1853098 (Newer (third generation) i.v. iron preparations (ferric carboxymaltose, ferric derisomaltose [FDI], ferumoxytol) have a more compact structure and exhibit different modes of iron release compared with their predecessors. This limits their pro-oxidant effect and potentially any resulting nephrotoxicity.) However, differences in safety profiles such as hypophosphatemia require further study and therapy should be tailored to the individual.)
52. Baliga R, Zhang Z, Baliga M, et al. In vitro and in vivo evidence suggesting a role for iron in cisplatin-induced nephrotoxicity. Kidney Int. 1998; 53(2):394–401. (Iron can increase the cisplatin-induced cytotoxicity. A critical role for iron in mediating tissue injury via hydroxyl radical (or a similar oxidant) in this model of nephrotoxicity.)
53. Walker VJ, Agarwal A. Targeting Iron Homeostasis in Acute Kidney Injury. Semin Nephrol. 2016 Jan; 36(1): 62–70. doi: 10.1016/j.semnephrol.2016.01.003
54. see 49*
55. Ganz T, Nemeth E. Iron Balance and the Role of Hepcidin in Chronic Kidney Disease. Semin Nephrol. 2016 Mar; 36(2): 87–93. doi: 10.1016/j.semnephrol.2016.02.001 (In chronic kidney disease, inflammation and impaired renal clearance increase plasma hepcidin, inhibiting duodenal iron absorption and sequestering iron in macrophages. These effects of hepcidin can cause systemic iron deficiency, decreased availability of iron for erythropoiesis, and resistance to endogenous and exogenous erythropoietin.) Iron toxicity may cause anemia?
56. see 51
57. Theodoropoulos G, Makkous A, Constantoulakis M. Lymph node enlargement after a single massive infusion of iron dextran. J. clin. Path. 1968; 21, 492-494. (Painful lymphadenopathy developed in eight female patients after massive infusions of iron dextran for sideropaenic anaemia. Fever, arthralgias, and malaise were also features of the clinical picture. Some swelling of lymph can last for 20 days.)
58. De Sousa M. Immune cell functions in iron overload. Clin. exp. Immunol. (1989) 75, 1-6 (The author predicted that the majority of the observations made in vitro have a counterpart in vivo, thus providing additional compelling evidence for the importance of iron as an immunoregulator.)
59. Walker Jr EM, Walker SM. Effects of iron overload on the immune system. Review Ann Clin Lab Sci. 2000 Oct;30(4):354-65. (It disrupts the entire immune system. Increased body stores of iron in various clinical situations may tip the immunoregulatory balance unfavorably to allow increased growth rates of cancer cells and infectious organisms, and complicate the clinical management of preexisting acute and chronic diseases.)
60. Espinosa J, Rehman U, Kaddouh F. A case of intravenous iron administration resulting in cerebral edema expansion. BMC Neurol 2023;23,209. https://doi.org/10.1186/s12883-023-03258-8
61. Liu R, Zhang H, Cheng S, et al. Association of Brain Iron Overload With Brain Edema and Brain Atrophy After Intracerebral Hemorrhage. Front Neurol. 2020;11:602413.
62. Jin L, Wang J, Zhao L, et al. Decreased serum ceruloplasmin levels characteristically aggravate nigral iron deposition in Parkinson’s disease. Brain. 2011; 134(Pt 1):50–8.
63. Salazar J, Mena N, Hunot S, et al. Divalent metal transporter 1 (DMT1) contributes to neurodegeneration in animal models of Parkinson’s disease. Proc Natl Acad Sci U S A. 2008;105(47):18578–18583.
64. Gaasch JA, Lockman PR, Geldenhuys WJ, et al. Brain iron toxicity: differential responses of astrocytes, neurons, and endothelial cells. Neurochem Res. 2007;32(7):1196–208.
65. Duce JA, Tsatsanis A, Cater MA, et al. Iron-export ferroxidase activity of β-amyloid precursor protein is inhibited by zinc in Alzheimer’s disease. Cell. 2010; 142(6):857–867.
66. Fukumoto S. FGF23-related hypophosphatemic rickets/osteomalacia: diagnosis and new treatment. J Mol Endocrinol. 2021; 66(2):R57–65.
67. Schaefer B, see 10*Vi
68. Tatiane V, see 9*
69. Tsay J, Yang Z, Ross FP, et al. Bone loss caused by iron overload in a murine model: importance of oxidative stress. Blood (2010) 116(14):2582–9. doi: 10.1182/blood-2009-12-260083.
70. Richmond HG: Induction of sarcoma in the rat by iron-dextran complex. BMJ. 1959;1:947–949.
71. Chanvorachote P, Luanpitpong S. Iron induces cancer stem cells and aggressive phenotypes in human lung cancer cells. Am J Physiol Cell Physiol. 2016; 310:C728–C739. Doi: https://doi.org/10.1152/ajpcell.00322.2015
72. Nelson RL. Dietary iron and colorectal cancer risk. Free Radic Biol Med. 1992;12:161–168. (Iron intake and the ingestion of associated foods that greatly affect iron bioavailability and absorption (phytate, tannin, ascorbate, and alcohol) vary widely between high-risk and low-risk countries as well as within the United States.)
73. Haggar FA and Boushey RP: Colorectal cancer epidemiology: Incidence, mortality, survival, and risk factors. Clin Colon Rectal Surg. 2009;22:191–197.
74. Wilson MJ, Harlaar JJ, Jeekel J, et al. Iron therapy as treatment of anemia: A potentially detrimental and hazardous strategy in colorectal cancer patients. Med Hypotheses. 2018;110:110–113.
75. Xue X and Shah YM: Intestinal iron homeostasis and colon tumorigenesis. Nutrients. 2013; 5:2333–2351.
76. Chua ACG, Klopcic B, Lawrance IC, et al. Iron: An emerging factor in colorectal carcinogenesis. World J Gastroenterol. 2010;16:663–672.
77. Kato I, Dnistrian AM, Schwartz M, et al. Iron intake, body iron stores and colorectal cancer risk in women: A nested case-control study. Int J Cancer. 1999;80:693–698.
78. Wilson MJ, Dekker JWT, Harlaar JJ, et al. The role of preoperative iron deficiency in colorectal cancer patients: Prevalence and treatment. Int J Colorectal Dis. 2017;32:1617–1624.
79. Castiella A, Múgica F, Zapata E, et al: Gender and plasma iron biomarkers, but not HFE gene mutations, increase the risk of colorectal cancer and polyps. Tumour Biol. 2015;36:6959–6963.
80. Joosten E, Meeuwissen J, Vandewinckele H and Hiele M: Iron status and colorectal cancer in symptomatic elderly patients. Am J Med. 2008;121:1072–1077.
81. Wilson MJ, Dekker JW, Bruns E, et al. Short-term effect of preoperative intravenous iron therapy in colorectal cancer patients with anemia: Results of a cohort study. Transfusion. 2018;58:795–803.
82. Laso-Morales M, Jericó C, Gómez-Ramírez S, et al. Preoperative management of colorectal cancer-induced iron deficiency anemia in clinical practice: Data from a large observational cohort. Transfusion. 2017;57:3040–3048.
83. Da Costa GG, Gomig TH, Kaviski R, et al. Comparative proteomics of tumor and paired normal breast tissue highlights potential biomarkers in breast cancer. Cancer Genomics Proteomics. 2015;12:251–261.
84. Stevens RG, Cologne JB, Nakachi K, et al. Body iron stores and breast cancer risk in female atomic bomb survivors. Cancer Sci. 2011;102:2236–2240.
85. Wang YF, Zhang J, Su Y, et al. G9a regulates breast cancer growth by modulating iron homeostasis through the repression of ferroxidase hephaestin. Nat Commun. 8:2742017. .
86. Kuban-Jankowska A, Sahu KK, Gorska-Ponikowska M, et al. Inhibitory activity of iron chelators ATA and DFO on MCF-7 breast cancer cells and phos-phatases PTP1B and SHP2. Anticancer Res. 2017;37:4799–4806.
87. Saha P, Yeoh BS, Xiao X, et al. Enterobactin, an iron chelating bacterial siderophore, arrests cancer cell proliferation. Biochem. Pharmacol. 2019;168:71–81. doi: 10.1016/j.bcp.2019.06.017.
88. Islam S, Hoque N, Nasrin N, Hossain M, Rizwan F, Biswas K, Asaduzzaman M, Rahman S, Hoskin DW, Sultana S, Lehmann C. Iron Overload and Breast Cancer: Iron Chelation as a Potential Therapeutic Approach. Life (Basel). 2022 Jun 27;12(7):963. doi: 10.3390/life12070963.
89. Komoto K, Nomoto T, El Muttaqien S, et al. Iron chelation cancer therapy using hydrophilic block copolymers conjugated with deferoxamine. Cancer Sci. 2021;112(1):410-421. https://www.doi.org/10.1111/cas.14607
90. Ridge CA, McErlean AM, Ginsberg MS. Epidemiology of lung cancer. Semin Intervent Radiol. 2013;30:93–98.
91. Wild P, Bourgkard E and Paris C: Lung cancer and exposure to metals: The epidemiological evidence. Methods Mol Biol. 2009;472:139–167.
92. Brookes MJ, Boult J, Roberts K, et al. A role for iron in Wnt signalling. Oncogene. 2008; 27:966–975.
93. Lovera-Leroux M, Crobeddu B, Kassis N, et al. The iron component of particulate matter is antiapoptotic: A clue to the development of lung cancer after exposure to atmospheric pollutants? Biochimie. 2015;118:195–206.
94. Bidoli E, Barbone F, Collarile P, et al. Residence in proximity of an iron foundry and risk of lung cancer in the municipality of trieste, Italy, 1995-2009. Int J Environ Res Public Health. 2015; 12:9025–9035.
95. Kew MC. Hepatic iron overload and hepatocellular carcinoma. Liver Cancer. 2014;3:31–40.
96. De Sanctis, V. Concise Review On The Frequency, Major Risk Factors And Surveillance Of Hepatocellular Carcinoma (Hcc) In ?-Thalassemias: Past, Present And Future Perspectives: Thalassaemia transfusion dependent, Hepatitis C, hepatocarcinoma”., Mediterranean Journal of Hematology and Infectious Diseases 2020;12(1), p. e2020006. doi: 10.4084/mjhid.2020.006.
97. Hino K, Yanatori I, Hara Y, Nishina S. Iron and liver cancer: an inseparable connection. The FEBS Journal. 2022;289:7810–7829. https://doi.org/10.1111/febs.16208
98. Song MK, Chung JS, Seol YM, et al. Elevation of serum ferritin is associated with the outcome of patients with newly diagnosed multiple myeloma. Korean Korean J Intern Med. 2009;24:368–373.
99. Strasser-Weippl K and Ludwig H: Ferritin as prognostic marker in multiple myeloma patients undergoing autologous transplantation. Leuk Lymphoma. 2014; 55:2520–2524.
100. Gu Z, Wang H, Xia J, et al. Decreased ferroportin promotes myeloma cell growth and osteoclast differentiation. Cancer Res. 2015;75:2211–2221.
101. Jakszyn P, Agudo A, Lujan-Barroso L, et al. 2012. Dietary intake of heme iron and risk of gastric cancer in the European prospective investigation into cancer and nutrition study. Int. J. Cancer 130:2654–63 (An positive association was found between heme iron intake and gastric cancer incidence. The cohort included 481,419 individuals with 444 cases of gastric cancer in 8.7 years of follow-up. Participants in the highest quartile of heme ingestion had a 70% higher risk of developing gastric cancer than those in the lowest quartile).
102. Kim JL, Lee D-H, Na YJ, et al. Iron chelator-induced apoptosis via the ER stress pathway in gastric cancer cells. Tumour Biol. 2016;37:9709–9719
103. de Juan D, Reta A, Castiella A, et al. HFE gene mutations analysis in Basque hereditary haemochromatosis patients and controls. Eur J Hum Genet. 2001;9:961–964.
104. Asberg A, Thorstensen K, Irgens WO, et al. Cancer risk in HFE C282Y homozygotes: Results from the HUNT 2 study. Scand J Gastroenterol. 2013;48:189–195.
105. Wu KJ, Polack A, Dalla-Favera R: Coordinated regulation of iron-controlling genes, H-ferritin and IRP2, by c-MYC. Science. 1999; 283:676–679.
106. Tonks NK: Protein tyrosine phosphatases: From genes, to function, to disease. Nat Rev Mol Cell Biol. 2006; 7:833–846.
107. Grosse SD, Rogowski WH, Ross LF, et al. Population screening for genetic disorders in the 21st century: Evidence, economics, and ethics. Public Health Genomics. 2010;13:106–115.
108. Bardou-Jacquet E, Morcet J, Manet G, et al. Decreased cardiovascular and extrahepatic cancer-related mortality in treated patients with mild HFE hemochromatosis. J Hepatol. 2015; 62:682–689.
109. Huang X: Iron overload and its association with cancer risk in humans: Evidence for iron as a carcinogenic metal. Mutat Res. 2003;533:153–171.
110. Stevens RG, Graubard BI, Micozzi MS, et al. Moderate elevation of body iron level and increased risk of cancer occurrence and death. Int. J. Cancer 1994. 56:364–69
111. Wu T, Sempos CT, Freudenheim JL, et al. Serum iron, copper and zinc concentrations and risk of cancer mortality in US adults. Ann. Epidemiol. 2004;14:195–201
112. see 72*.
113. see 80*
114. Sesink AL, Termont DS, Kleibeuker JH, Van der Meer R. 1999. Red meat and colon cancer: the cytotoxic and hyperproliferative effects of dietary heme. Cancer Res. 59:5704–9
115. Sesink AL, Termont DS, Kleibeuker JH, Van der Meer R. 2000. Red meat and colon cancer: Dietary haem, but not fat, has cytotoxic and hyperproliferative effects on rat colonic epithelium. Carcinogenesis 21:1909–15
116. Bastide NM, Chenni F, Audebert M, Santarelli RL, Tache S, et al. 2015. A central role for heme iron in colon carcinogenesis associated with red meat intake. Cancer Res. 75:870–79
117. Cross AJ, Leitzmann MF, Gail MH, Hollenbeck AR, Schatzkin A, Sinha R. 2007. A prospective study of red and processed meat intake in relation to cancer risk. PLOS Med. 4:e325
118. Toyokuni S, Mori T, Dizdaroglu M. 1994. DNA base modifications in renal chromatin of Wistar rats treated with a renal carcinogen, ferric nitrilotriacetate. Int. J. Cancer 57:123–28 (ferric nitrilotriacetate is intimately linked to carcinogenesis through the induction of damage to cellular components, including lipids, proteins, and principally DNA).
119. WEINBERG, ED Iron withholding: a defense against infection and neoplasia. Physiol. Rev. 1984;64,65.
120. Cosialls E, Hage RE, Dos Santos L, et al. Ferroptosis: Cancer Stem Cells Rely on Iron until “to Die for” Cells. 2021 Nov;10(11):2981.
121. Lui GY, Obeidy P, Ford SJ, et al. 2013. The iron chelator, deferasirox, as a novel strategy for cancer treatment: oral activity against human lung tumor xenografts and molecular mechanism of action. Mol. Pharmacol. 83:179–90
122. Zhao R, Planalp RP, Ma R, et al. 2004. Role of zinc and iron chelation in apoptosis mediated by tachpyridine, an anti-cancer iron chelator. Biochem. Pharmacol. 67:1677–88
123. Roemhild K, von Maltzahn F, Weiskirchen R, et al. Iron metabolism: Pathophysiology and Pharmacology. Trends Pharmacol Sci. 2021 August 01;42(8):640–656. doi:10.1016/j.tips.2021.05.001. (In patients with iron overload, such as HH, the risk of HCC (a liver cancer) is increased by up to 200-fold.)
124. Dev S, Babitt JL. Overview of Iron Metabolism in Health and Disease. Hemodial Int. 2017 June;21(Suppl 1):S6–S20. doi:10.1111/hdi.12542.
125. Feldman HI, Santanna J, Guo W, et al. Iron administration and clinical outcomes in hemodialysis patients. J Am Soc Nephrol. 2002; 13: 734-744 (There is increasing data to suggest that infective and adverse-event risks may be related to the intensity and frequency of IV iron dosing)
126. Shah AA. Donovan K, Seeley C, et al. Risk of Infection Associated With Administration of Intravenous Iron: A Systematic Review and Meta-analysis. JAMA Netw Open. 2021;4(11):e2133935. doi:10.1001/jamanetworkopen.2021.33935) (all kinds of infections)
127. Litton E, Xiao J, Ho KM. Safety and efficacy of intravenous iron therapy in reducing requirement for allogeneic blood transfusion: systematic review and meta-analysis of randomised clinical trials. BMJ. 2013; 347: f4822 (A recent meta-analysis of randomized controlled trials evaluating IV iron use (often administered as frequent boluses) in patients with varying infective risk profiles found IV iron to be associated with 30% greater risk of infection compared to oral or no iron therapy.
128. Gonçalves JL, Silva MCA, Roma EH, et al. Iron intake is positively associated with viral load in antiretroviral naïve Brazilian men living with HIV. Mem Inst Oswaldo Cruz. 2019; 114: e190350. Doi: 10.1590/0074-02760190350
129. Chapoutot C, Esslimani M, Joomaye Z, et al. Liver iron excess in patients with hepatocellular carcinoma developed on viral C cirrhosis. Gut. 2000 May; 46(5): 711–714. doi: 10.1136/gut.46.5.711 (Liver iron deposition was more frequent and more important in viral C cirrhotic patients with hepatocellular carcinoma than in cancer free controls. Liver iron overload seems to contribute to the development of hepatocellular carcinoma in patients with viral C cirrhosis.)
130. Salama KM, Ibrahim OM, Ahmed M. Liver Enzymes in Children with beta-Thalassemia Major: Correlation with Iron Overload and Viral Hepatitis. Open Access Maced J Med Sci. 2015 Jun 15; 3(2): 287–292. doi: 10.3889/oamjms.2015.059 (Iron overload is a main leading cause of elevated liver enzymes, and presence of hepatitis-C virus infection is significantly related to the increased iron overload.)
131. Ward JL, Torres-Gonzalez M, Ammons CBM. The Influence of Viral Infections on Iron Homeostasis and the Potential for Lactoferrin as a Therapeutic in the Age of the SARS-CoV-2 PandemicNutrients. 2022 Aug; 14(15): 3090. doi: 10.3390/nu14153090
132. Romina Mancinelli, Luigi Rosa, Antimo Cutone, et al. Viral Hepatitis and Iron Dysregulation: Molecular Pathways and the Role of Lactoferrin. Molecules. 2020 Apr; 25(8): 1997. doi: 10.3390/molecules25081997
133. Chhabra R, Saha A, Chamani A, et al. Iron Pathways and Iron Chelation Approaches in Viral, Microbial, and Fungal Infections. Pharmaceuticals (Basel) 2020 Oct; 13(10):275. (The studies adopt a strategy which is diametrically opposite to the old thinking of using iron infusion to manage anemia for cancer patients.)
134. Drakesmith H, Prentice A. Viral infection and iron metabolism. Nat Rev
Microbiol (2008) 6(7):541–52. doi: 10.1038/nrmicro1930
135. Wessling-Resnick M. Crossing the Iron Gate: Why and How Transferrin Receptors Mediate Viral Entry. Annu Rev Nutr. 2018 Aug 21;38:431–458. doi: 10.1146/annurev-nutr-082117-051749 (Because both the host and pathogen require iron, the innate immune response carefully orchestrates control over iron metabolism to limit its availability during times of infection. Nutritional iron deficiency can impair host immunity, while iron overload can cause oxidative stress to propagate harmful viral mutations. An emerging enigma is that many viruses use the primary gatekeeper of iron metabolism, the transferrin receptor, as a means to enter cells. Why and how this iron gate is a viral target for infection are the focus of this review.)
136. Murray MJ, Murray AB, Murray MB, Murray CJ. The adverse effect of iron repletion on the course of certain infections. Br Med J. 1978;2(6145):1113–1135. [bacterial]
137. Sazawal S, Black RE, Ramsan M, et al. Effects of routine prophylactic supplementation with iron and folic acid on admission to hospital and mortality in preschool children in a high malaria transmission setting: community-based, randomised, placebo-controlled trial. Lancet. 2006;367(9505):133–143.
138. Soofi S, Cousens S, Iqbal SP, et al. Effect of provision of daily zinc and iron with several micronutrients on growth and morbidity among young children in Pakistan: a cluster-randomised trial. Lancet. 2013; 382(9886):29–40.
139. David V, Francis C, Babitt JL. Ironing out the cross talk between FGF23 and inflammation. Am J Physiol Renal Physiol. 2017; 312(1):F1–F8. (The protective effects of iron deficiency for malaria, diarrheal illnesses, and tuberculosis in the developing world is supported by the increased rate of these infections and their associated morbidity and mortality.
140. Weinberg ED. Iron and infection. Microbiol Rev (1978) 42(1):45–66. doi: 10.1128/MMBR.42.1.45-66.1978
141. La Carpia, F, Wojczyk BS, Annavajhala MK. Transfusional iron overload and intravenous iron infusions modify the mouse gut microbiota similarly to dietary iron. npj Biofilms Microbiomes 2019;5, 26. https://doi.org/10.1038/s41522-019-0097-2. (These iron interventions have consistent and reproducible effects on the murine gut microbiota; specifically, relative abundance of the Parabacteroides and Lactobacillus genera negatively correlate with increased iron stores, whereas members of the Clostridia class positively correlate with iron stores regardless of the route of iron administration.)
142. Ku?micka W, Manda-Handzlik A, Mroczek A, et al. Iron excess affects release of neutrophil extracellular traps and reactive oxygen species but does not influence other functions of neutrophils. Immunology & Cell Biology. 2021:100(2):87-100). https://doi.org/10.1111/imcb.12509 (Escherichia coli)
143. Darton TC, Blohmke CJ, Giannoulatou E, et al. Rapidly Escalating Hepcidin and Associated Serum Iron Starvation Are Features of the Acute Response to Typhoid Infection in Humans. PLoS Negl Trop Dis. 2015; 9:e0004029.
144. Arezes J, Jung G, Gabayan V, et al. Hepcidin-induced hypoferremia is a critical host defense mechanism against the siderophilic bacterium Vibrio vulnificus. Cell Host Microbe. 2015; 17:47–57.
145. Kim DK, Jeong JH, Lee JM, et al. Inverse agonist of estrogen-related receptor γ controls Salmonella typhimurium infection by modulating host iron homeostasis. Nat Med. 2014; 20:419–424.
146. Brookhart MA, Freburger JK, Ellis AR, Wang L. Infection risk with bolus versus maintenance iron supplementation in hemodialysis patients. J Am Soc Nephrol. 2013; 24:1151-1158. (the authors studied iron dosing patterns in a retrospective cohort of 117,050 prevalent hemodialysis patients and found that administration of large boluses of IV iron for repleting iron deficiency was associated with increased infection-related hospitalization or death (adjusted hazard ratio, 1.08; 95% confidence interval, 1.05-1.11) compared with smaller doses of IV iron maintenance therapy. The risk of infection-related hospitalization was increased further in patients who had experienced infection within the past month.
147. Rozen-Zvi B, Gafter-Gvili A, Paul M, et al. Intravenous versus oral iron supplementation for the treatment of anemia in CKD: systematic review and meta-analysis. Am J Kidney Dis. 2008; 52: 897-906 (Unfortunately, similar trials in patients with CKD seldom report bacterial infections as an end point. Iron toxicity can diminish patient’s ability to defend against microbial infections. Based on mice model study, iron overload inhibits the release of NETs and ROS production in neutrophils isolated from mice fed a high-iron diet.
148. David V, Martin A, Isakova T, et al. Inflammation and functional iron deficiency regulate fibroblast growth factor 23 production. Kidney Int. 2016; 89(1):135–146. [bone]
149. Dietz JV, Fox JL, Khalimonchuk O. Down the Iron Path: Mitochondrial Iron Homeostasis and Beyond. Cells. 2021 Aug 25;10(9):2198. doi: 10.3390/cells10092198.
150. Anelli T, Sitia R. Protein quality control in the early secretory pathway. EMBO J. 2008;27:315–27.
151. Rauen U, Springer A, Weisheit D, et al. Assessment of chelatable mitochondrial iron by using mitochondrion-selective fluorescent iron indicators with different iron-binding affinities. ChemBioChem 2007, 8, 341–352;
152. Nie G, Sheftel AD, Kim SF, et al. Overexpression of mitochondrial ferritin causes cytosolic iron depletion and changes cellular iron homeostasis. Blood 2005;105, 2161–2167).
153. Bell S, Rigas AS, Magnusson MK. A genome-wide meta-analysis yields 46 new loci associating with biomarkers of iron homeostasis Commun Biol 2021;4,156. https://doi.org/10.1038/s42003-020-01575-z.
154. Miller LD, Coffman LG, Chou JW, et al. An iron regulatory gene signature predicts outcome in breast cancer. Cancer Res 2011;71:6728‐6737.
155. Zhang P. Influence of Foods and Nutrition on the Gut Microbiome and Implications for Intestinal Health Int J Mol Sci. 2022 Sep; 23(17): 9588.
156. Shi HB, Li XD, Jiang JT, et al. Serum ferritin is elevated in advanced non-small cell lung cancer patients and is associated with efficacy of platinum-based chemotherapy. J Cancer Res Ther. 2014; 10: 681-5.
157. Cohen LA, Gutierrez L, Weiss A, et al. Serum ferritin is derived primarily from macrophages through a nonclassical secretory pathway. Blood. 2010; 116: 1574-84;
158. Alkhateeb AA, Han B, Connor JR. Ferritin stimulates breast cancer cells through an iron-independent mechanism and is localized within tumor-associated macrophages. Breast Cancer Res Treat. 2013;137:733-44.
159. Frost JN, Wideman SK, Preston AE. Plasma iron controls neutrophil production and function. Sci Adv. 2022 Oct; 8(40): eabq5384. doi: 10.1126/sciadv.abq5384 (Mice given mHep to remove iron from liver had fewer neutrophils and eosinophils, but unchanged Ly6C+ and Ly6C−monocyte frequency, in the spleen and blood.)
160. Szebeni see 12*.
161. Szebeni J. Complement activation-related pseudoallergy: a new class of drug-induced acute immune toxicity. Review Toxicology. 2005 Dec 15;216(2-3):106-21. doi: 10.1016/j.tox.2005.07.023 (symptom diversity)
162. Weiss G, Goodnough LT. Anemia of chronic disease. The New England journal of medicine. 2005; 352: 1011-23.
163. McLaren GD, McLaren CE, Adams PC, et al. Hemochromatosis and Iron Overload Screen (HEIRS) Study Research Investigators. Clinical manifestations of hemochromatosis in HFE C282Y homozygotes identified by screening. Can J Gastroenterol. 2008 Nov;22(11):923-30.
164. Carrón-Herrero A, Fernández-Lozano C, Botella Carretero J, et al. Delayed Hypersensitivity Reaction to Iron Salts: From Diagnosis to Desensitization, J Investig Allergol Clin Immunol. 2022;32(6):496-498. doi: 10.18176/jiaci.0789.) The delay in presentment of adverse reactions is the main reason for failure to conduct diagnosis and failure to manage this deadly adverse reaction.
165. Firoz, BF;Goldberg, LH;Landau, J. et al. Eosinophilic fasciitis secondary to intravenous iron infusions. Dermatology Online Journal. 2010;16(5). https://doi.org/10.5070/D39sm798wc (A 43-year-old woman presented with edema of the hand, soft-tissue swelling, joint stiffness, and intermittent, etc. four weeks after receiving intravenous iron infusions.)
166. Wu J, Zha P. Clinical trials cannot provide sufficient accuracy for studying weak factors necessary for curing chronic diseases. Glob J Cancer Ther. 2022;8(1):021-033. DOI: 10.17352/2581-5407.000044;
167. Wu J, Zha P. Flawed foundation is the root cause of failure of medicine and precludes cures for chronic diseases. Glob J Cancer Ther 2023;9(1): 001-019. DOI: https://dx.doi.org/10.17352/2581-5407.000050
168. see 163 *.
169. Vinchi F, Castagna A, da Silva MC, et al. Intravenous Iron Promotes Low-Grade Inflammation in Anemic Patients By Triggering Macrophage Activation. Blood. 2019;134 (Supplement_1): 957. https://doi.org/10.1182/blood-2019-132235 (!fever may be caused by iron infusion)
170. Perry LJ, Guralp O, Al-Niaimi A. False positive PET–CT scan and clinical examination in a patient with locally advanced vulvar cancer. Gynecologic Oncology Reports 4 (2013) 29–31. (all 20 SUV lit lymth nodes are false-positive.)
171. Boellaard R. Standards for PET Image Acquisition and Quantitative Data Analysis. J Nucl Med 2009;50:11S–20S. DOI: 10.2967/jnumed.108.057182.
172. Wiyaporn K, Tocharoenchai C, Pusuwan P, et al. Factors affecting standardized uptake value (SUV) of positron emission tomography (PET) imaging with 18F-FDG. J Med Assoc Thai. 2010 Jan;93(1):108-14.
173. Carter KR, Kotlyarov E. Common Causes of False Positive F 18 FDG PET/CT Scans in Oncology. Brazilian archives of biology and technology. September 2007;50:29-35,
174. Schapiro R, Moncayo VM, Meisel JL. Case report of lymph node activation mimicking cancer progression: A false positive F 18 FDG PET CT after COVID-19 vaccination. Current Problems in Cancer: Case Reports 4 (2021) 100092. (Vaccine can cause false positive report)
175. Li S, Zheng Q, Ma Y. Implications of False Negative and False Positive Diagnosis in Lymph Node Staging of NSCLC by Means of 18 F-FDG PET/CT. PLoS ONE 2013;8(10): e78552. doi:10.1371/journal.pone.0078552 (Postoperatively, 45.5% (41/90) patients were confirmed as false positive cases.)
176. Zhu A, Lee D, and Shim H, et al. Metabolic PET Imaging in Cancer Detection and Therapy Response. Semin Oncol. 2011 February; 38(1):55–69. doi:10.1053/j.seminoncol.2010.11.012
177. Cramer FM, Chuang HH, Miranda RN, Lee HJ. False-Positive Positron Emission Tomography After Combined-Modality Induction Therapy in a Patient With Newly Diagnosed Early-Stage Bulky Classic Hodgkin Lymphoma. Journal of Oncology Practice. 2019;15(9)499-502. DOI https://doi.org/10.1200/JOP.19.00258
178. Guarin GE, da Costa Dourado CM, Chief Editor: Emmanuel C Besa. Transfusion-Induced Iron Overload Clinical Presentation. In Drugs & Diseases Hematology. https://emedicine.medscape.com/article/1389732-clinical?form=fpf#showall (?ascite and effusion both)
179. Rahman K. Effects of garlic on platelet biochemistry and physiology. Mol Nutr Food Res. 2007 Nov;51(11):1335-44. DOI: 10.1002/mnfr.200700058
180. Andrew J Innes, Gwen Kennedy, Margaret McLaren, et al. Dark chocolate inhibits platelet aggregation in healthy volunteers. Platelets. 2003 Aug;14(5):325-7. Doi: 10.1080/0953710031000123681. DOI: 10.1080/0953710031000123681
181. Moroi MK, Loloi J, Songdej N. Cranberry supplementation as a cause of major intraoperative bleeding during vascular surgery due to aspirin-like platelet inhibition. Blood Coagul Fibrinolysis. 2020 Sep;31(6):402-404. doi: 10.1097/MBC.0000000000000912.
182. Ostertag LM, O’Kennedy N, Kroon PA. Impact of dietary polyphenols on human platelet function – A critical review of controlled dietary intervention studies Mol. Nutr. Food Res 2010, 54, 60–81. DOI 10.1002/mnfr.200900172
183. Dutta-Roy AK, Crosbie L, Gordon MJ. Effects of tomato extract on human platelet aggregation in vitro. Platelets ( 2001 ) 12, 218– 227
184. Tahir N, Zahra F. Neutrophilia. [Updated 2023 Apr 27]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. https://www.ncbi.nlm.nih.gov/books/NBK570571/
185. Herrero-Cervera, A., Soehnlein, O. & Kenne, E. Neutrophils in chronic inflammatory diseases. Cell Mol Immunol 19, 177–191 (2022). https://doi.org/10.1038/s41423-021-00832-3 (However, in chronic inflammation, the role of neutrophils is less well understood and has been described as either beneficial or detrimental, causing tissue damage and enhancing the immune response.)
186. Dumitru CA, Lang S, Brandau S. Modulation of neutrophil granulocytes in the tumor microenvironment: mechanisms and consequences for tumor progression. Semin Cancer Biol. 2013;23(3):141–148. doi: 10.1016/j.semcancer.2013.02.005.
187. Tazzyman S, Niaz H, Murdoch C. Neutrophil-mediated tumour angiogenesis: subversion of immune responses to promote tumour growth. Semin Cancer Biol. 2013;23(3):149–158. doi: 10.1016/j.semcancer.2013.02.003.
188. Tang L, Cai M, Zhou Yao, etc. Acute stress induces an inflammation dominated by innate immunity represented by neurtophils in mince, Frontier In Immunology. Front. Immunol. 13:1014296. doi: 10.3389/fimmu.2022.1014296 (In a study involving mice, it was found that acute stress led to a significant increase in the number of neutrophils in peripheral blood, while the number of T cells and B cells decreased significantly).
189. Ince LM, Weber J, Scheiermann C. Control of Leukocyte Trafficking by Stress-Associated Hormones. Front. Immunol. 9:3143. doi: 10.3389/fimmu.2018.03143.
190. Tsukamoto K, Machida K. Effects of life events and stress on neutrophil functions in elderly men. Immunity & Ageing. 2012, 9:13 http://www.immunityageing.com/content/9/1/13. (Systemic administration of sympathetic neurotransmitters adrenaline and noradrenaline, increases neutrophil numbers in the bloodstream, but has different effects on other leukocyte populations. The blood count depends on how much of the neutrophils are detached from blood vessel walls.
191. Solanki DL, Blackburn BC. Spurious leukocytosis and thrombocytopenia. A dual phenomenon caused by clumping of platelets in vitro. JAMA. 1983 Nov 11;250(18):2514-5.
192. Savage RA. Pseudoleukocytosis due to EDTA-induced platelet clumping. Am J Clin Pathol. 1984 Mar;81(3):317-22.
193. Krishna R, Antoine MH, Rudrappa M. Pleural Effusion. [Updated 2023 Mar 18]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK448189/
194. Freter S, Davidman M, Lipman M, Bercovitch D. Pulmonary edema: atypical anaphylactoid reaction to intravenous iron dextran. Am J Nephrol. 1997;17(5):477-9. doi: 10.1159/000169146.
195. Klockars M, Weber T, Tanner P, et al. Pleural fluid ferritin concentrations in human disease. Journal of Clinical Pathology 1985;38:818-824. (The greatest differences, with up to 100 times more ferritin in the pleural fluid, were found for patients with rheumatoid pleurisy, malignant effusions, and empyema.)
196. Grott K, Chauhan S, Dunlap JD. Atelectasis. [Updated 2023 Jun 19]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK545316/
197. Woodring JH, Reed JC. Types and mechanisms of pulmonary atelectasis. J Thorac Imaging. 1996 Spring;11(2):92-108.
198. Maini R, Nagalli S. Lymphadenopathy. [Updated 2023 Aug 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK558918/
199. Lee J, Kim YK, Seo YY. Clinical Characteristics of False-Positive Lymph Node on Chest CT or PET-CT Confirmed by Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration in Lung Cancer. Tuberc Respir Dis (Seoul). 2018 Oct; 81(4): 339–346. (biopsy procedure).
200. Zimmerman L, McKeon B. Osteomalacia. [Updated 2023 Nov 12]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK551616/
201. Sayani FA, Lal A, Tasian GE, Kidney Stones in Transfusion-Dependent Thalassemia: Prevalence and Risk Factors. Open Journal of Urology, 2022;12,4,
202. Scales, C.D., Tasian, G.E., Schwaderer, A.L., Goldfarb, D.S., Star, R.A. and Kirkali, Z. (2016) Urinary Stone Disease: Advancing Knowledge, Patient Care, and Population Health. Clinical Journal of the American Society of Nephrology: CJASN, 11, 1305-1312. https://doi.org/10.2215/CJN.13251215
203. Wong, P., Fuller, P.J., Gillespie, M.T., Kartsogiannis, V., Strauss, B.J., Bowden, D. and Milat, F. (2013) Thalassemia Bone Disease: The Association between Nephrolithiasis, Bone Mineral Density and Fractures. Osteoporosis International: A Journal Established as Result of Cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA, 24, 1965-1971.
204. Ricchi, P., Ammirabile, M., Costantini, S., Di Matola, T., Spasiano, A., Genna, M.L., Cinque, P. and Prossomariti, L. (2012) Splenectomy Is a Risk Factor for Developing Hyperuricemia and Nephrolithiasis in Patients with Thalassemia Intermedia: A Retrospective Study. Blood Cells, Molecules & Diseases, 49, 133-135. https://doi.org/10.1016/j.bcmd.2012.05.012
205. Zhang C, Wang B, Zhao X, Li X, Lou Z, Chen X, Zhang F. Iron deficiency accelerates intervertebral disc degeneration through affecting the stability of DNA polymerase epsilon complex. Am J Transl Res. 2018 Nov 15;10(11):3430-3442. PMID: 30662597; PMCID: PMC6291718.
206. Wang W, Jing X, Du T. Iron overload promotes intervertebral disc degeneration via inducing oxidative stress and ferroptosis in endplate chondrocytes. Free Radical Biology and Medicine 190 (2022) 234–246
207. McKnight CL, Burns B. Pneumothorax. [Updated 2023 Feb 15]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK441885/
208. Vecchio LD, see 11*
209. Awan O, Wu J, Eisenberg R. Imaging of Focal Sclerotic Bone Lesions.
Contemporary Diagnostic Radiology. February 28, 2015;38(5):1-8.
210. Bouchette P, Boktor SW. Paget Bone Disease. [Updated 2023 Nov 12]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK430805/
211. Sethi A, Taylor DL, Ruby G. Calcification of the abdominal aorta is an under-appreciated cardiovascular disease risk factor in the general population. Front Cardiovasc Med. 2022; 9: 1003246. Published online 2022 Oct 6. doi: 10.3389/fcvm.2022.1003246.
212. Uyama O, Yoshimoto Y, Yamamoto Y, Kawai A. Bone Changes and Carotid Atherosclerosis in Postmenopausal Women. Stroke. 1997;28:1730–1732; https://doi.org/10.1161/01.STR.28.9.1730
213. Chiejina M, Kudaravalli P, Samant H. Ascites. [Updated 2023 Aug 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470482/
214. Tie J, Jia WY, Gou X. Portal Hypertension Refractory Ascites Caused by Secondary Hemochromatosis J Clin Transl Hepatol. 2023;11(4):987-990. doi: 10.14218/JCTH.2022.00418. (A 46-year-old male patient who was repeatedly infused with red blood cells for anemia secondary to osteopetrosis suffered from refractory ascites.)
215. Shizukuda Y, Rosing DR. Iron overload and arrhythmias: Influence of confounding factors. J Arrhythm. 2019 Aug;35(4): 575–583. doi: 10.1002/joa3.12208
216. Kaye SB, Owen M. Cardiac arrhythmias in thalassaemia major: evaluation of chelation treatment using ambulatory monitoring. Br Med J. 1978;1(6109):342.
217. Gujja P, Rosing DR, Tripodi DJ, Shizukuda Y. Iron overload cardiomyopathy: better understanding of an increasing disorder. J Am Coll Cardiol. 2010;56(13):1001–12.
218. Lekawanvijit S, Chattipakorn N. Iron overload thalassemic cardiomyopathy: iron status assessment and mechanisms of mechanical and electrical disturbance due to iron toxicity. Can J Cardiol. 2009;25(4):213–8.
219. Fuleihan GE, Clines GA, Hu MI, et al. Treatment of Hypercalcemia of Malignancy in Adults: An Endocrine Society Clinical Practice Guideline, The Journal of Clinical Endocrinology & Metabolism, Volume 108, Issue 3, March 2023, Pages 507–528, https://doi.org/10.1210/clinem/dgac621
220. Weinberg ED. Risks and Side Effects of Iron Therapy: Iron therapy and cancer. Kidney International. 1999;55(69):131-134. https://doi.org/10.1046/j.1523-1755.1999.055Suppl.69131.x
221. Arthur CK, Isbistor JP: Iron deficiency: Misunderstood, misdiagnosed and mistreated. Drugs 33:171–182, 1987
222. Alizadeh BZ, Njajou OT, Houwing-Duistermaat JJ, et al. Does bilirubin protect against hemochromatosis gene (HFE) related mortality? Am J Med Genet A. 2004 Aug 15;129A(1):39-43. doi: 10.1002/ajmg.a.30163.
223. Davin-Regli A, Pagès JM. Enterobacter aerogenes and Enterobacter cloacae; versatile bacterial pathogens confronting antibiotic treatment. Front Microbiol. 2015 May 18;6:392. doi: 10.3389/fmicb.2015.00392. PMID: 26042091; PMCID: PMC4435039.
224. Bono MJ, Leslie SW, Reygaert WC. Uncomplicated Urinary Tract Infections. [Updated 2023 Nov 13]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470195/
225?. EVERSON TC, COLE WH. Spontaneous Regression of Cancer: Preliminary Report. Annuals of Surgery. 1956;336- 381. (Although over 600 cases of tumor regression published; Estimated it occurs once in 100,000 cases of cancer and Boyers,5 once in 80,000. This is absolutely wrong.)
225. Challis GB, Stam HJ. The Spontaneous Regression of Cancer: A review of cases from 1900 to 1987, Acta Oncologica. 1990;29:5, 545-550, DOI: 10.3109/02841869009090048
226. ?arkovi? N, Jaganjac M, ?arkovi? K, et al. Spontaneous Regression of Cancer: Revealing Granulocytes and Oxidative Stress as the Crucial Double-edge Sword. Front. Biosci. (Landmark Ed) 2022; 27(4):119 https://doi.org/10.31083/j.fbl2704119 (Hence, in animal models spontaneous regression of cancer could be mediated by rapid inflammatory response of granulocytes, acting against cancer mostly as innate immune response. Neutrophil elevation: The number of spontaneous regression cases reported yearly increased, and almost 90 cases were reported only in 2021)
227. Kucerova P, Cervinkova M. Spontaneous regression of tumour and the role of microbial infection – possibilities for cancer treatment. Anti-Cancer Drugs 2015. 27:269–277 (The author has previously reported that in 80% of the cases of malignant tumours, for which no alternate form of treatment was available, survival was longer than 5 years.)
228. Niakan B. Common Factors among Some of the Reported Cases of the Spontaneous Remission and Regression of Cancer after Acute Infections. Niakan. Int J Cancer Clin Res 2019, 6:112 DOI: 10.23937/2378-3419/1410112
229. Radha G, Lopus M. The spontaneous remission of cancer: Current insights and therapeutic significance. Translational Oncology 2021;14,101166
230. Ren JG, Seth P, Ye H, et al. Citrate suppresses tumor growth in multiple models through inhibition of glycolysis, the tricarboxylic acid cycle and the IGF‐1R pathway. Sci Rep 2017;7:4537
231. ?Ascorbate therapy specifically targets cancer cells via an iron-dependent mechanism and is clinically effective as a single agent [27] and in combination therapy [113, 177].
232. Cameron E, Pauling L. Supplemental ascorbate in the supportive treatment of cancer: reevaluation of prolongation of survival times in terminal human cancer. PNAS 1978; 75:4538–42
233. Ma Y, Chapman J, Levine M, Polireddy K, Drisko J, Chen Q.. High-dose parenteral ascorbate enhanced chemosensitivity of ovarian cancer and reduced toxicity of chemotherapy. Sci. Transl. Med. 2014;6:222ra18
234. Zheng Q, Zhao Y, Guo J, et al. Iron overload promotes mitochondrial fragmentation in mesenchymal stromal cells from myelodysplastic syndrome patients through activation of the AMPK/MFF/ Drp1 pathway. Cell Death Dis (2018) 9(5):515. doi: 10.1038/s41419-018-0552-7
235. Cabantchik ZI. Labile iron in cells and body fluids: physiology, pathology, and pharmacology. Front. Pharmacol. 2014;5,45 https://doi.org/10.3389/fphar.2014.00045.
236. Muckenthaler MU, Rivella S, Hentze MW, Galy B. A Red Carpet for Iron Metabolism. Cell. 2017 Jan 26;168(3):344-361. doi: 10.1016/j.cell.2016.12.034. PMID: 28129536; PMCID: PMC5706455.
237. Office of Dietary Supplements, NIH. Iron fact sheet for consumer. https://ods.od.nih.gov/factsheets/Iron-Consumer/
238. Current Dietary Guidelines: Food Sources of Iron (Standard Portions)
Dietary Guidelines for Americans. Iron: Nutrient-dense Food and Beverage Sources, Amounts of Iron and Energy per Standard Portion. https://www.dietaryguidelines.gov/resources/2020-2025-dietary-guidelines-online-materials/food-sources-select-nutrients/food-1
239. Shu W, Baumann BH, Song Y, et al. Iron Accumulates in Retinal Vascular Endothelial Cells But Has Minimal Retinal Penetration After IP Iron Dextran Injection in Mice. Invest Ophthalmol Vis Sci. 2019 Oct 1;60(13):4378-4387. doi: 10.1167/iovs.19-28250.
240. Loh A, Hadziahmetovic M, Dunaief JL. Iron homeostasis and eye disease. Biochim Biophys Acta. 2009 Jul;1790(7):637-49. doi: 10.1016/j.bbagen.2008.11.001 (a broad range of eye disease).
241. Gabrielsen JS, Lamb DJ, Lipshultz LI. Iron and a Man's Reproductive Health: the Good, the Bad, and the Ugly. Curr Urol Rep. 2018 Jun 1;19(8):60. doi: 10.1007/s11934-018-0808-x.
242. Tian C, Zhao J, Xiong Q, Yu H, Du H. Secondary iron overload induces chronic pancreatitis and ferroptosis of acinar cells in mice. Int J Mol Med. 2023 Jan;51(1):9. doi: 10.3892/ijmm.2022.5212.
243. Tsai C-J, Leitzmann MF, Willett WC, Giovannucci EL. Heme and non-heme iron consumption and risk of gallstone disease in men. The American Journal of Clinical Nutrition 2007;85(2)518-522
244. Jenkitkasemwong S, Wang CY, Coffey R, et al. SLC39A14 is required for the development of hepatocellular iron overload in murine models of hereditary hemochromatosis. Cell Metab. 2015;22:138–50.
245. Kassebaum N, Jasasaria R, Naghavi N, et al. A systemic analysis of global anemia burden from 1990 to 2010. Blood. 2014;123(5):615–624.
246. Al-Kuraishy HM, Al-Gareeb AI. Comparison of deferasirox and deferoxamine effects on iron overload and immunological changes in patients with blood transfusion-dependent β-thalassemia. Asian J Transfus Sci. 2017;11(1):13-17. https://www.doi.org/10.4103/0973-6247.200768
247. Camaschella C, Nai A. Ineffective erythropoiesis and regulation of iron status in iron loading anaemias. Br J Haematol. 2016; 172(4):512–523.
248. Foggo V, Cavenagh J. Malignant causes of fever of unknown origin. Clin Med (Lond). 2015 Jun;15(3):292-4. doi: 10.7861/clinmedicine.15-3-292. PMID: 26031983; PMCID: PMC4953117.
249. Wagner C, Kotsougiani D, Pioch M, et al. T lymphocytes in acute bacterial infection: increased prevalence of CD11b(+) cells in the peripheral blood and recruitment to the infected site. Immunology. 2008 Dec;125(4):503-9. doi: 10.1111/j.1365-2567.2008.02863.x.
250. Hamad H, Mangla A. Lymphocytosis. [Updated 2023 Jul 17]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK549819/
251. Barton JC, Wiener HW, Acton RT, Go RC. Total blood lymphocyte counts in hemochromatosis probands with HFE C282Y homozygosity: relationship to severity of iron overload and HLA-A and -B alleles and haplotypes. BMC Blood Disord. 2005 Jul 25;5:5. doi: 10.1186/1471-2326-5-5.
252. Kuo KL, Hung SC, Wei YH, Tarng DC. Intravenous iron exacerbates oxidative DNA damage in peripheral blood lymphocytes in chronic hemodialysis patients. J Am Soc Nephrol. 2008 Sep;19(9):1817-26. doi: 10.1681/ASN.2007101084.
選擇“Disable on www.wenxuecity.com”
選擇“don't run on pages on this domain”
