HFE H63D & VO2 max

September 20, 2024
by

SMOKE EM IF YOU GOT EM

The HFE H63D is a single-nucleotide polymorphism in the HFE gene (c.187C>G, rs1799945), which results in the substitution of a histidine for an aspartic acid at amino acid position 63 of the HFE protein (p.His63Asp). HFE participates in the regulation of iron absorption.

Homozygous H63D variant can occasionally be the cause of hemochromatosis. It is also associated with the occurrence of other conditions LIKE HYPOTRANSFERRINEMIA, LIVER dysfunction, bone and joint issues, diabetes mellitus, heart DISEASE, HORMONE, PORPHYRIA cutanea TARDA (PCT), infertility, STROKE, NEURODEGENERATIVE AND BRAIN DAMAGES, SOME cancers, venous and peripheral artery disease.

I asked Copilot which cancers are associated with H63D and got this response:

The H63D mutation, associated with hereditary hemochromatosis, has been linked to an increased risk of several types of cancer. Specifically, individuals with this mutation have a higher risk of developing hepatocellular carcinoma (a type of liver cancer), colorectal cancer, and breast cancer.

General health impacts

The primary risk associated with the H63D mutation is brain damage, as iron accumulation can cause oxidation within affected cells, ultimately leading to cell death and scarring of the brain tissue.

Another potential consequence is abnormal levels of tau proteins and alpha-synuclein, which play a role in conditions like Alzheimer’s, Lewy body dementia, and Parkinson’s; patients homozygous for the H63D mutation show a higher risk of earlier signs of cognitive impairment and earlier onset of dementias compared to individuals with normal or heterozygous genotypes.[citation needed] 

A study in 2020 predicted that the H63D variant may be a risk factor for incidental amyotrophic lateral sclerosis in a Han Chinese population.

Some individuals with the homozygous H63D variant may show signs of heart disease, cardiomyopathies, and disturbances in the calcium channels in particular.

The homozygous H63D variant is an indicator of the iron metabolism disorder hemochromatosis, which may increase the risk of developing a fatty liver. In patients with a cirrhotic liver, the mutation can increase the rate of liver cancer.

H63D syndrome

H63D syndrome is a very rare clinical phenotype based on a homozygous mutation of the HFE gene. This mutation is associated with diverse health issues, however H63D syndrome is the only known specific expression of a homozygous HFE-H63D mutation to date. The homozygous HFE-H63D mutation is the cause of classic and treatable hemochromatosis in only 6.7% of its carriers. H63D syndrome is independently a distinct entity, and the incidence in homozygous carriers of the H63D mutation is approximately 10%.

Pathomechanism

Typically, laboratory tests show an excessive and static transferrin saturation based on a relative deficiency of transferrin. The transferrin value is pre- and postprandial static low. Thus, the body does not respond to nutritive iron supplementation by providing more transferrin. This allows free iron of non-transferrin bound type (NTBI, labile iron pool) can enter various parenchymal tissues and trigger degenerative changes there by oxidation cascades. Iron overload primarily affects nerve cells in the substantia nigra and basal ganglia. Here, a slowly progressive degeneration occurs. In addition, many H63D syndrome patients experience nonspecific activation of the inert immune systems, which can additionally lead to spontaneously occurring, passive autoimmune reactions of variable type and severity.

H63D syndrome symptoms

  • Variable motor dysfunction, possibly including Parkinson’s symptoms late in the course.
  • Postural instability analogous to Parkinson’s disease.
  • Narcolepsy, often with cataplexy – when manifestation of degenerative and irreversible brain damage has already occurred.
  • Cognitive dysfunction: Often highly severe and usually primarily obsessive in nature, compatible with dysfunction of the basal ganglia. They are often misrecognized – especially in the early phase of the disease – in the sense of a misdiagnosis as “mental suffering”. If thought disorders are in the foreground, a timely diagnosis is therefore often delayed.
  • Tic disorders: variable Tourette’s-like tics occurring with a strongly fluctuating course.
  • Hyperkinesias, sometimes with self-injuries.
  • Disturbance of REM sleep with risk of self-injury.
  • Dementia of varying severity from mild cognitive impairment to full-blown dementia, most compatible with Lewy body dementia. Clinically relevant changes occur in 30% to 60% of H63D patients, depending on the study. Variability is due to nonstandardized measurement procedures and cut-off values, especially in mild cognitive impairment.
  • Cognitive impairments: This aspect is often masked by performance reserves over time (months to years), especially in previously cognitively strong patients, but can lead to significant failures in daily and occupational functioning under high sensory and complex content input.
  • Decline in intelligence quotients despite preserved selective performance in areas that can be relatively well delineated diagnostically.
  • Impairment of executive functions with preserved long-term memory. The occurrence or worsening of narcolepsy with a decrease in tic symptomatology is indicative of progressive damage to brain tissue, mainly in the region of the substantia nigra.
  • Cardiac damage and dysfunction, especially conduction defects and arrhythmias, occasionally progressing to heart failure
  • Liver damage (even early in the course, often an unexplained steatosis).
  • Excessive episodes of the inert part of the immune system with highly variable autoimmune reactions, including periods of decreased defense of the adaptive immune system.
  • Fibrosis in various organ systems, including the skin.
  • Impaired motility in the digestive system, usually constipation, less commonly bloating.
  • Testicular atrophy, erectile dysfunction and degeneration of penile tissue degeneration (shrinking of the shaft) in male patients, sometimes with unspecific degenerative signs on sonography like calcifications. (Copilot says shrinking penis is not a thing)
  • Skin symptoms of variable nature (including impetigo, pruritus, hyper-responsiveness, hidradenitis suppurativa, etc.).
  • Rarely: kidney involvement, eye diseases due to NTBI-induced oxidative processes, hearing loss, etc.
  • Rather later in the course, with already structurally altered substantia nigra: urge incontinence in all its manifestations.
  • Chronic eosinophilia with possible structural damage to the heart.
  • Disorders of adrenal and other endocrine organ function due to oxidative-related inflammatory processes with functional or structural organ damage caused by infiltration processes in the adrenal cortex region. (primary adrenal insufficiency).
  • Subsequently, there is clinically relevant dysfunction of the HPA axis as well as adrenaline synthesis in the adrenal medulla with erratic adrenaline excesses.
  • Due to the variety of symptoms, the syndrome is usually diagnosed relatively late, especially if all relevant parameters of iron metabolisms are not obtained by laboratory diagnosis.

Laboratory

The typical constellation of findings is indicative: The patients show a postprandial non-responsive and too low and static transferrin level (hypotransferrinemia) with high transferrin saturation (usually > 55 %) and low ferritin value. Multiple tests are obligatory due to physiologically induced fluctuations. Mild persistent eosinophilia and basophilia are sometimes found in parallel.

Imaging

On transcranial sonography, the substantia nigra presents as in Parkinson’s disease hyperechogenic, but the symptoms need not be identical. With rare exceptions, MRI remains unremarkable. The scintigraphy (DAT scan) may also be abnormal. Due to radiation exposure and advances in the field of sonography, DAT scans are now mostly used only in the context of clinical trials for this condition.

Pathohistology

There is deposition of free iron in the brain and other tissues. NTBI iron cannot be stained in histology (e.g., with the (Berlin Blue staining). This is a common source of error or reason for false-negatives.

Therapies

No causal treatment for H63D syndrome is currently (2023) available. Free iron not bound to proteins cannot be removed from the body by phlebotomy and related procedures. Instead, the patient would merely suffer a further drop in his already usually low ferritin level. Consequently, dialysis and iron chelators are also ineffective and are more likely to provoke lethal side effects than to improve the clinical picture. Various drugs can be used to alleviate some symptoms – some in off-label use. In addition, medical assistive devices such as orthotics, hard hats, walkers, or wheelchairs are useful.

Impact on athletic performance in healthy individuals

A 2020 study revealed that the homozygous H63D variant (as well as the heterozygous one) is significantly higher in elite endurance athletes comparing to ethnically matched controls in Russian and Japanese populations and is associated with high V̇O2max in male athletes.

Abstract

Purpose: Iron is an important component of the oxygen-binding proteins and may be critical to optimal athletic performance. Previous studies have suggested that the G allele of C/G rare variant (rs1799945), which causes H63D amino acid replacement, in the HFE is associated with elevated iron indexes and may give some advantage in endurance-oriented sports. The aim of the present study was to investigate the association between the HFE H63D polymorphism and elite endurance athlete status in Japanese and Russian populations, aerobic capacity and to perform a meta-analysis using current findings and three previous studies.

Methods: The study involved 315 international-level endurance athletes (255 Russian and 60 Japanese) and 809 healthy controls (405 Russian and 404 Japanese). Genotyping was performed using micro-array analysis or by PCR. VO2max in 46 male Russian endurance athletes was determined using gas analysis system.

Results: The frequency of the iron-increasing CG/GG genotypes was significantly higher in Russian (38.0 vs 24.9%; OR 1.85, P = 0.0003) and Japanese (13.3 vs 5.0%; OR 2.95, P = 0.011) endurance athletes compared to ethnically matched controls. The meta-analysis using five cohorts (two French, Japanese, Spanish, and Russian; 586 athletes and 1416 controls) showed significant prevalence of the CG/GG genotypes in endurance athletes compared to controls (OR 1.96, 95% CI 1.58-2.45; P = 1.7 × 10-9). Furthermore, the HFE G allele was associated with high V̇O2max in male athletes [CC: 61.8 (6.1), CG/GG: 66.3 (7.8) ml/min/kg; P = 0.036].

Conclusions: We have shown that the HFE H63D polymorphism is strongly associated with elite endurance athlete status, regardless ethnicities and aerobic capacity in Russian athletes.

Keywords: Athletes; Endurance performance; Gene; Genotype; Hemochromatosis.

Semenova EA, Miyamoto-Mikami E, Akimov EB, Al-Khelaifi F, Murakami H, Zempo H, Kostryukova ES, Kulemin NA, Larin AK, Borisov OV, Miyachi M, Popov DV, Boulygina EA, Takaragawa M, Kumagai H, Naito H, Pushkarev VP, Dyatlov DA, Lekontsev EV, Pushkareva YE, Andryushchenko LB, Elrayess MA, Generozov EV, Fuku N, Ahmetov II. The association of HFE gene H63D polymorphism with endurance athlete status and aerobic capacity: novel findings and a meta-analysis. Eur J Appl Physiol. 2020 Mar;120(3):665-673. doi: 10.1007/s00421-020-04306-8. Epub 2020 Jan 22. PMID: 31970519; PMCID: PMC7042188.

V̇O2 max (also maximal oxygen consumption, maximal oxygen uptake or maximal aerobic capacity) is the maximum rate of oxygen consumption attainable during physical exertion. The name is derived from three abbreviations: “V̇” for volume (the dot over the V indicates “per unit of time” in Newton’s notation), “O2” for oxygen, and “max” for maximum and usually normalized per kilogram of body mass. A similar measure is V̇O2 peak (peak oxygen consumption), which is the measurable value from a session of physical exercise, be it incremental or otherwise. It could match or underestimate the actual V̇O2 max. Confusion between the values in older and popular fitness literature is common. The capacity of the lung to exchange oxygen and carbon dioxide is constrained by the rate of blood oxygen transport to active tissue.

Note: I read about the H63D at the transferrin page which says: An increased plasma transferrin level is often seen in patients with iron deficiency anemia, during pregnancy, and with the use of oral contraceptives, reflecting an increase in transferrin protein expression. When plasma transferrin levels rise, there is a reciprocal decrease in percent transferrin iron saturation, and a corresponding increase in total iron binding capacity in iron deficient states.

A decreased plasma transferrin level can occur in iron overload diseases and protein malnutrition. An absence of transferrin results from a rare genetic disorder known as atransferrinemia, a condition characterized by anemia and hemosiderosis in the heart and liver that leads to heart failure and many other complications as well as to H63D syndrome.

Studies reveal that a transferrin saturation (serum iron concentration ÷ total iron binding capacity) over 60 percent in men and over 50 percent in women identified the presence of an abnormality in iron metabolism (Hereditary hemochromatosis, heterozygotes and homozygotes) with approximately 95 percent accuracy. This finding helps in the early diagnosis of Hereditary hemochromatosis, especially while serum ferritin still remains low.

The retained iron in Hereditary hemochromatosis is primarily deposited in parenchymal cells, with reticuloendothelial cell accumulation occurring very late in the disease. This is in contrast to transfusional iron overload in which iron deposition occurs first in the reticuloendothelial cells and then in parenchymal cells. This explains why ferritin levels remain relatively low in Hereditary hemochromatosis, while transferrin saturation is high. Transferrin and its receptor have been shown to diminish tumour cells when the receptor is used to attract antibodies.

  • Macedo MF, de Sousa M (March 2008). “Transferrin and the transferrin receptor: of magic bullets and other concerns”. Inflammation & Allergy – Drug Targets. 7 (1): 41–52. doi:10.2174/187152808784165162. PMID 18473900.

Note: I asked Copilot if smokers have more or less transferrin and got this response:

Smokers generally tend to have lower levels of transferrin compared to non-smokers. This is because smoking can lead to chronic inflammation and liver damage, both of which can reduce the production of transferrin. Transferrin is a protein that binds and transports iron in the blood, and its levels are influenced by various factors including iron status, inflammation, and liver function

Note: I asked Copilot why smokers have less H63D mutation and got this response:

The lower prevalence of H63D mutations among smokers could be due to several factors, including the complex interactions between genetics and environmental influences like smoking. Smoking has been shown to affect iron metabolism and oxidative stress, which might influence the expression or detection of certain genetic mutations.

Additionally, smoking can lead to various health issues that might mask or complicate the diagnosis of hereditary hemochromatosis, making it less likely for smokers to be identified as carriers of the H63D mutation.

Copilot mentions iron metabolism, oxidative stress and vitamin c depletion (as to why smokers have less incidence of the H63D, hemochromatosis and most if not all of the associated malfunctions/damage). That is the case no matter how I phrase the questions. When I pointed out that smokers also have less scurvy, it suggested smokers often consume more vitamin C rich foods or supplements to counteract depletion (depletion due to oxidative stress). It also mentioned chronic bleeding as a reason smokers have less iron. Most smokers are not chronic bleeders as far as I know. Somebody needs to tell them. It is an interesting note for females of a certain age…or all ages. Copilot says “post-menopausal women are more likely to develop symptoms of hemochromatosis than premenopausal women because menstruation acts as a natural way to shed excess iron from the body. Once that stops, iron can accumulate more rapidly.” The treatment for these problems historically and presently is phlebotomy (historically involving bloodletting and leeches). Another interesting note I want to include here involves other nutrient deficiencies attributed to smoking including b12 (which is from animal products?) and folate which “are important for red blood cell production.” I asked a lot of questions, some of them more than once and drafted this early in that process. Other things to look into include PH, Temperature and Circadian rhythm.

The Transferrin page mentions a condition called atransferrinemia: Atransferrinemia is characterized by anemia and hemosiderosis in the heart and liver. The iron damage to the heart can lead to heart failure. The anemia is typically microcytic and hypochromic (the red blood cells are abnormally small and pale). Atransferrinemia was first described in 1961 and is extremely rare, with only ten documented cases worldwide. The presentation of this disorder entails anemia, arthritis, hepatic anomalies, and recurrent infections are clinical signs of the disease. Iron overload occurs mainly in the liver, heart, pancreas, thyroid, and kidney.

Transferrin is a serum transport protein that transports iron to the reticuloendothelial system for utilization and erythropoiesis, since there is no transferrin in atransferrinemia, serum free iron cannot reach reticuloendothelial cells and there is microcytic anemia. Also, this excess iron deposits itself in the heart, liver and joints, and causes damage. Ferritin, the storage form of iron gets secreted more into the bloodstream so as to bind with the excessive free iron and hence serum ferritin levels rise in this condition [medical citation needed] In terms of genetics of atransferrinemia researchers have identified mutations in the TF gene as a probable cause of this genetic disorder in affected people.

There are two forms of this condition that causes an absence of transferrin in the affected individual: Acquired atransferrinemia and Congenital atransferrinemia. The treatment of atransferrinemia is apotransferrin, the missing protein without iron. After the dissociation of iron, transferrin is called apotransferrin. Apotransferrin remains bound to its receptor because it has a high affinity for its receptors at a reduced pH. It recycles back to the plasma membrane, still bound to its receptor. Iron treatment is detrimental as it does not correct the anemia and is a cause of secondary hemochromatosis. In nephrotic syndrome, urinary loss of transferrin, along with other serum proteins such as thyroxine-binding globulin, gammaglobulin, and anti-thrombin III, can manifest as iron-resistant microcytic anemia.

Barton, James C.; Edwards, Corwin Q. (2001). Hemochromatosis: Genetics, Pathophysiology, Diagnosis and Treatment. Cambridge University Press. p. 212. ISBN 9780521593809.

  • Ogun AS, Adeyinka A. Biochemistry, Transferrin. [Updated 2022 Nov 16]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK532928/
  • Hoffman, Ronald; Benz, Edward J. Jr.; Silberstein, Leslie E.; Heslop, Helen; Weitz, Jeffrey; Anastasi, John (2012). Hematology: Diagnosis and Treatment. Elsevier Health Sciences. p. 443. ISBN 978-1455740413.
  • Gelderman MP, Baek JH, Yalamanoglu A, Puglia M, Vallelian F, Burla B, Vostal J, Schaer DJ, Buehler PW. Reversal of hemochromatosis by apotransferrin in non-transfused and transfused Hbbth3/+ (heterozygous B1/B2 globin gene deletion) mice. Haematologica. 2015 May;100(5):611-22. doi: 10.3324/haematol.2014.117325. Epub 2015 Jan 23. PMID: 25616571; PMCID: PMC4420210.

I am reposting the entire section or most of it but the most interesting part of all that at this time is the mention of PH which is something else to look at. I asked Copilot how smoking affects PH or acid base homeostasis and got this answer:

Smoking can significantly impact the body’s pH and acid-base homeostasis through several mechanisms:

  1. Respiratory Acidosis: Smoking can lead to chronic obstructive pulmonary disease (COPD) and other respiratory issues, which impair the lungs’ ability to expel carbon dioxide (CO₂). The buildup of CO₂ in the blood increases carbonic acid levels, leading to respiratory acidosis, a condition where the blood becomes too acidic.
  2. Oxidative Stress: The chemicals in cigarette smoke increase oxidative stress, which can disrupt the balance of acids and bases in the body. This oxidative stress can lead to inflammation and further complications in maintaining pH balance.
  3. Kidney Function: Smoking can also affect kidney function, which plays a crucial role in regulating acid-base balance by excreting hydrogen ions and reabsorbing bicarbonate. Impaired kidney function can lead to metabolic acidosis or alkalosis
  4. Buffer Systems: The body’s buffer systems, such as the bicarbonate buffer system, work to neutralize excess acids or bases. Smoking can interfere with these systems, making it harder for the body to maintain a stable pH.

Maintaining a balanced pH is crucial for normal cellular functions, and disruptions can lead to severe health issues

References

  1. Olynyk JK, Trinder D, Ramm GA, Britton RS, Bacon BR (September 2008). “Hereditary hemochromatosis in the post-HFE era”. Hepatology. 48 (3): 991–1001. doi:10.1002/hep.22507. PMC 2548289. PMID 18752323.
  2. “Hemochromatosis: Causes”. Mayo Foundation for Medical Education and Research (MFMER).
  3. den Dunnen JT, Dalgleish R, Maglott DR, Hart RK, Greenblatt MS, McGowan-Jordan J, Roux AF, Smith T, Antonarakis SE, Taschner PE (June 2016). “HGVS Recommendations for the Description of Sequence Variants: 2016 Update”. Human Mutation. 37 (6): 564–9. doi:10.1002/humu.22981. hdl:11343/291098. PMID 26931183.
  4. Fujii H, Takagaki N, Yoh T, et al. (2008). “Non-prescription supplement-induced hepatitis with hyperferritinemia and mutation (H63D) in the HFE gene”. Hepatology Research. 38 (3): 319–23. doi:10.1111/j.1872-034X.2007.00266.x. PMID 17944940. S2CID 30008466.
  5. Castiella A, Urreta I, Zapata E, et al. (2019). “H63/H63D genotype and the H63D allele are associated in patients with hyperferritinemia to the development of metabolic syndrome”. Eur. J. Intern. Med. (Letter to the Editor). 72: 106–107. doi:10.1016/j.ejim.2019.11.021. PMID 31796245. S2CID 208623301.
  6. Raszeja-Wyszomirska J, Kurzawski G, Zawada I, et al. (2010). “HFE gene mutations in patients with alcoholic liver disease. A prospective study from northwestern Poland”. Polish Archives of Internal Medicine. 120 (4): 127–31. doi:10.20452/pamw.905. PMID 20424537.
  7. Valenti L, Fracanzani AL, Bugianesi E, et al. (2010). “HFE Genotype, Parenchymal Iron Accumulation, and Liver Fibrosis in Patients With Nonalcoholic Fatty Liver Disease”. Gastroenterology. 138 (3): 905–12. doi:10.1053/j.gastro.2009.11.013. hdl:2318/85426. PMID 19931264. S2CID 13091615.
  8. Ellervik C, Tybjaerg-Hansen A, Appleyard M, et al. (2007). “Hereditary hemochromatosis genotypes and risk of ischemic stroke”. Neurology. 68 (13): 1025–31. doi:10.1212/01.wnl.0000257814.77115.d6. PMID 17389307. S2CID 43908712.
  9. Liu Y, Lee SY, Neely E, et al. (2011). “Mutant HFE H63D Protein Is Associated with Prolonged Endoplasmic Reticulum Stress and Increased Neuronal Vulnerability”. J. Biol. Chem. 286 (15): 13161–70. doi:10.1074/jbc.M110.170944. PMC 3075663. PMID 21349849.
  10. Mitchell RM, Lee SY, Simmons Z, et al. (2011). “HFE polymorphisms affect cellular glutamate regulation”. Neurobiol. Aging. 32 (6): 1114–23. doi:10.1016/j.neurobiolaging.2009.05.016. PMID 19560233. S2CID 22440350.
  11. “H63D – The Other Mutation” (PDF). Iron Disorders Institute nanograms. 2010. Archived from the original (PDF) on 2018-10-24. Retrieved 2019-12-22.
  12. Nandar W, Connor JR (2011). “HFE Gene Variants Affect Iron in the Brain”. J. Nutr. 141 (4): 729S–739S. doi:10.3945/jn.110.130351. PMID 21346098.
  13. Hall EC 2nd, Lee SY, Simmons Z, et al. (2010). “Prolyl-peptidyl isomerase, Pin1, phosphorylation is compromised in association with the expression of the HFE polymorphic allele, H63D” (PDF). Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease. 1802 (4): 389–95. doi:10.1016/j.bbadis.2010.01.004. PMID 20060900. S2CID 46729333.
  14. Bartzokis G, Lu PH, Tishler TA, et al. (2010). “Prevalent Iron Metabolism Gene Variants Associated with Increased Brain Ferritin Iron in Healthy Older Men”. J. Alzheimer’s Dis. 20 (1): 333–41. doi:10.3233/JAD-2010-1368. PMC 3119253. PMID 20164577.
  15. Guerreiro RJ, Bras JM, Santana I, et al. (2006). “Association of HFE common mutations with Parkinson’s disease, Alzheimer’s disease and mild cognitive impairment in a Portuguese cohort”. BMC Neurology. 6 (24): 24. doi:10.1186/1471-2377-6-24. PMC 1534050. PMID 16824219.
  16. Dekker MC, Giesbergen PC, Njajou OT, et al. (2003). “Mutations in the hemochromatosis gene (HFE), Parkinson’s disease and parkinsonism”. Neurosci. Lett. 348 (2): 117–9. doi:10.1016/S0304-3940(03)00713-4. PMID 12902032. S2CID 32076298.
  17. Borie C, Gasparini F, Verpillat P, et al. (2002). “Association study between iron-related genes polymorphisms and Parkinson’s disease”. J. Neurol. 249 (7): 801–4. doi:10.1007/s00415-002-0704-6. PMID 12140659. S2CID 22293375.
  18. Akbas N, Hochstrasser H, Deplazes J, et al. (2006). “Screening for mutations of the HFE gene in Parkinson’s disease patients with hyperechogenicity of the substantia nigra”. Neurosci. Lett. 407 (1): 16–9. doi:10.1016/j.neulet.2006.07.070. PMID 16935420. S2CID 45492253.
  19. Zhang QQ, Jiang H, Li CY, Liu YL, Tian XY (September 2020). “H63D CG genotype of HFE is associated with increased risk of sporadic amyotrophic lateral sclerosis in a single population”. Journal of Integrative Neuroscience. 19 (3): 495–499. doi:10.31083/j.jin.2020.03.131. PMID 33070529.
  20. Adams PC, Pankow JS, Barton JC, et al. (2009). “HFE C282Y Homozygosity Is Associated With Lower Total and Low-Density Lipoprotein Cholesterol: The Hemochromatosis and Iron Overload Screening Study”. Circ. Cardiovasc. Genet. 2 (1): 34–7. doi:10.1161/CIRCGENETICS.108.813089. PMID 20031565.
  21. Franchini M (2006). “Hereditary iron overload: Update on pathophysiology, diagnosis, and treatment”. Am. J. Hematol. 81 (3): 202–9. doi:10.1002/ajh.20493. PMID 16493621.
  22. Castiella A, Zapata E, Zubiaurre L, et al. (2015). “Impact of H63D mutations, magnetic resonance and metabolic syndrome among outpatient referrals for elevated serum ferritin in the Basque Country”. Annals of Hepatology. 14 (3): 333–9. doi:10.1016/S1665-2681(19)31272-4. PMID 25864213.
  23. Jin F, Qu L, Shen X (2010). “Association between C282Y and H63D mutations of the HFE gene with hepatocellular carcinoma in European populations: a meta-analysis”. J. Exp. Clin. Cancer Res. 29 (1): 18. doi:10.1186/1756-9966-29-18. PMC 2845109. PMID 20196837.
  24. Machado MV, Ravasco P, Martins A, et al. (2009). “Iron homeostasis and H63D mutations in alcoholics with and without liver disease”. World Journal of Gastroenterology. 15 (1): 106–11. doi:10.3748/wjg.15.106. PMC 2653287. PMID 19115475.
  25. Kelley et al Iron overload is rare in patients homozygous for the H63D mutation Can J Gastroenterol Hepatol 2014
  26. Preprint: Incidence of a clinically relevant H63D syndrome in carriers of a homozygous mutation of HFE gene H63D, accessed 09/05/2022
  27. Séguéla et al Eosinophilic cardiac disease: Molecular, clinical and imaging aspects Arch Cardiovasc Dis 2015
  28. Banaszkiewicz et al. Endocrine disorders in patients with hereditary hemochromatosis European Journal of Translational and Clinical Medicine, 2018
  29. Charmandari et al. Adrenal insufficiency The Lancet 2014
  30. Lazar, M., Seideman D., Schuster G., Diamandis, C. (2022). Endocrinology: Patients suffering from H63D syndrome are at high risk to develop clinically relevant endocrine abnormalities affecting their adrenal glands as well as their HPA and SAM axes. https://doi.org/10.5281/zenodo.7269988
  31. [Wirkstoff aktuell – Eine Information der KBV im Rahmen des § 73 (8) SBG V in Zusammenarbeit mit der Arzneimittelkommission der Deutschen Ärzteschaft: Deferasirox (Exjade)], Ausgabe 5-2008 (in German]p)
  32. Seideman et al. Preprint: Injury protection strategies for H63D syndrome patients suffering from cataplexy 2021
  33. Semenova EA, Miyamoto-Mikami E, Akimov EB, Al-Khelaifi F, Murakami H, Zempo H, Kostryukova ES, Kulemin NA, Larin AK, Borisov OV, Miyachi M, Popov DV, Boulygina EA, Takaragawa M, Kumagai H, Naito H, Pushkarev VP, Dyatlov DA, Lekontsev EV, Pushkareva YE, Andryushchenko LB, Elrayess MA, Generozov EV, Fuku N, Ahmetov II (March 2020). “The association of HFE gene H63D polymorphism with endurance athlete status and aerobic capacity: novel findings and a meta-analysis”. European Journal of Applied Physiology. 120 (3): 665–673. doi:10.1007/s00421-020-04306-8. PMC 7042188. PMID 31970519.
  34. Clemente C. J.; Withers P. C.; Thompson G. G. (2009). “Metabolic rate and endurance capacity in Australian varanid lizards (Squamata; Varanidae; Varanus)”. Biological Journal of the Linnean Society. 97 (3): 664–676. doi:10.1111/j.1095-8312.2009.01207.x.
  35. Dlugosz, Elizabeth M.; Chappell, Mark A.; Meek, Thomas H.; Szafrańska, Paulina; Zub, Karol; Konarzewski, Marek; Jones, James H.; Bicudo, Eduardo; Nespolo, Roberto F.; Careau, Vincent; Garland, Theodore (2013). “Phylogenetic analysis of mammalian maximal oxygen consumption during exercise” (PDF). Journal of Experimental Biology. 216 (24): 4712–4721. doi:10.1242/jeb.088914. PMID 24031059. S2CID 15686903.
  36. Smirmaul, BP; Bertucci, DR; Teixeira, IP (2013). “Is the VO2max that we measure really maximal?”. Frontiers in Physiology. 4: 203. doi:10.3389/fphys.2013.00203. PMC 3733001. PMID 23935584.

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