HFE and Modern-Day Bloodletting #GeneOTW

Editor’s note: This post is the first in our “Gene of the Week” series. Learn more about it here.

Armed with leeches, scalpels, and scarificators, medical practitioners (and their patients) once trusted bloodletting as a valid, sensible remedy for common ailments.  In the time before “germs” existed, physicians thought that disease derived from an imbalance of certain bodily fluids—including blood.  Today, belief in this theory of “body humors”, and the consequent use of bloodletting as a restorative cure-all (Got a headache?  Put a leech on it!), is largely dismissed as an ill-conceived, archaic practice.  Even so, early doctors weren’t totally wrong; bloodletting is still considered a legitimate medical treatment for specific conditions—most notably, hemochromatosis.

Antique bloodletting tools from the 19th century. (photo by Anagoria, CC-BY)

With an estimated genetic prevalence of 1 in 200,1 hereditary hemochromatosis is the most common single-gene disorder for patients of European descent.2 Initial symptoms include fatigue, sexual dysfunction, and arthritis, and if left untreated, can progress to cirrhosis, diabetes, and heart failure.3  All this is caused by chronic over-accumulation of iron in the body, resulting from autosomal recessive inheritance of a mutation in the HFE gene.4  Recent (and controversial) evidence further suggests that HFE mutations also increase risk for neurodegenerative diseases,5678 and can even impair memory.9

3D structure of HFE. (image by Emw, CC-BY-SA )

Normally, HFE (from High Iron, Fe) protein helps regulate the proper balance of iron levels in the body.  Iron is required for essential biological processes like oxygen transport, but in excess, can be cytotoxic and cause oxidative stress.1011  Though the exact mechanisms remain unknown, HFE may act as a sensor for unbound iron, and can accordingly maintain iron homeostasis by affecting transcription of hepcidin,12131415 a hormone in the blood that blocks 1) uptake of dietary iron from the blood and 2) release of iron from internal storage.16

In hemochromatosis, mutated HFE results in a hepcidin deficiency,1718 and thus elevated iron levels through uncontrolled absorption of dietary iron and excessive release of stored iron.  To relieve symptoms, the primary treatment for hemochromatosis simply reduces iron overload—via bloodletting.19 In fact, each unit of blood withdrawn (500mL) contains an estimated 250 mg iron,2021 which is comparable to the amount found in 15 lbs of steak!  Regularly scheduled blood withdrawals decrease iron levels not only through loss of iron-containing red blood cells, but also through stimulation of new red blood cell production, a process that utilizes (and importantly, binds) iron from released stores. Indeed, some theories propose that monthly blood loss via menstruation partially protects women from developing hemochromatosis!2223

Today, nearly twenty years since the HFE gene was first discovered,24 treatment of hemochromatosis is effective and straightforward, but the precise biological mechanisms underlying disease pathology remain a mystery.  Although genetic mutation of HFE is relatively common25 and easily identified, clinical expression of the disease is more poorly understood.  Disease progression also depends on a growing list of genetic and environmental factors (including sex, diet, and alcohol consumption),262728 and not everyone with the HFE mutation (even homozygotes) will develop hemochromatosis.29 In fact, the mutation is so common (and disease expression so variable) that occasionally, livers from HFE^-/- patients are accidentally used in organ transplant to normal patients!30  Given that 39% of Caucasians are heterozygous carriers for an HFE mutation,31 it’s  increasingly important to better characterize the role of HFE—in both normal and mutant conditions.  In the meantime, if you do decide to follow 19th century medical advice… just forgo the leeches, and make a blood donation instead!

1. Adams PC, Reboussin DM, Barton JC, McLaren CE, Eckfeldt JH, McLaren GD, Dawkins FW, Acton RT, Harris EL, Gordeuk VR, Leiendecker-Foster C,Speechley M, Snively BM, Holup JL, Thomson E, Sholinsky P; Hemochromatosis and Iron Overload Screening (HEIRS) Study Research Investigators.(2005) Hemochromatosis and iron-overload screening in a racially diverse population. N Engl J Med. 352(17):1769-1778. doi: 10.1056/NEJMoa041534. (Pubmed) (PDF) [↩]
2. Leitman SF. (2013) Hemochromatosis: The new blood donor. Hematology. 2013:645-650. doi: 10.1182/asheducation-2013.1.645.(Pubmed) (PDF) [↩]
3. Leitman SF. (2013) Hemochromatosis: The new blood donor. Hematology. 2013:645-650. doi: 10.1182/asheducation-2013.1.645.(Pubmed) (PDF) [↩]
4. Feder JN, Gnirke A, Thomas W, Tsuchihashi Z, Ruddy DA, Basava A, Dormishian F, Domingo R Jr, Ellis MC, Fullan A, Hinton LM, Jones NL, Kimmel BE,Kronmal GS, Lauer P, Lee VK, Loeb DB, Mapa FA, McClelland E, Meyer NC, Mintier GA, Moeller N, Moore T, Morikang E, Prass CE, Quintana L, Starnes SM, Schatzman RC, Brunke KJ, Drayna DT, Risch NJ, Bacon BR, Wolff RK. (1996). A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet. 13:399-408. doi:10.1038/ng0896-399. (Pubmed)  [↩]
5. Johnstone D and Milward EA. (2010) Molecular genetic approaches to understanding the roles and regulation of iron in brain health and disease. J Neurochem. 113(6):1387-402. doi: 10.1111/j.1471-4159.2010.06697.x. (Pubmed) (PDF)  [↩]
6. Nandar W and Connor JR. (2011) HFE gene variants affect iron in the brain. J Nutr. 141(4):729S-739S. doi: 10.3945/jn.110.130351. (Pubmed) (PDF)  [↩]
7. Guerreiro RJ, Bras JM, Santana I, Januario C, Santiago B, Morgadinho AS, Ribeiro MH, Hardy J, Singleton A, Oliveira C. (2006) Association of HFE common mutations with Parkinson’s disease, Alzheimer’s disease and mild cognitive impairment in a Portuguese cohort. BMC Neurol. 6:24. doi:10.1186/1471-2377-6-24. (Pubmed) (PDF)  [↩]
8. Pulliam JF, Jennings CD, Kryscio RJ, Davis DG, Wilson D, Montine TJ, Schmitt FA, Markesbery WR. (2003) Association of HFE mutations with neurodegeneration and oxidative stress in Alzheimer’s disease and correlation with APOE. Am J Med Genet B Neuropsychiatr Genet. doi:10.1002/ajmg.b.10069. 119B(1):48-53. (Pubmed)  [↩]
9. Ali-Rahmani F, Grigson PS, Lee S, Neely E, Connor JR, Schengrund CL. (2013) H63D mutation in hemochromatosis alters cholesterol metabolism and induces memory impairment. Neurobiol Aging. 35(6): 1511.e1-1511.e12. doi: 10.1016/j.neurobiolaging.2013.12.014. (Pubmed) [↩]
10. Johnstone D and Milward EA. (2010) Molecular genetic approaches to understanding the roles and regulation of iron in brain health and disease. J Neurochem. 113(6):1387-402. doi: 10.1111/j.1471-4159.2010.06697.x. (Pubmed) (PDF)  [↩]
11. Nandar W and Connor JR. (2011) HFE gene variants affect iron in the brain. J Nutr. 141(4):729S-739S. doi: 10.3945/jn.110.130351. (Pubmed) (PDF)  [↩]
12. Ruchala P and Nemeth E. (2014) The pathophysiology and pharmacology of hepcidin. Trends Pharmacol Sci. 35(3):155-161. doi: 10.1016/j.tips.2014.01.004. (Pubmed) (PDF)  [↩]
13. Goswami T and Andrews NC. (2006) Hereditary hemochromatosis protein, HFE, interaction with transferrin receptor 2 suggests a molecular mechanism for mammalian iron sensing. J Biol Chem. 281:28494-8. doi:10.1074/jbc.C600197200. (Pubmed) (PDF)  [↩]
14. Rishi G, Crampton EM, Wallace DF, Subramaniam VN. (2013) In situ proximity ligation assays indicate the hemochromatosis proteins Hfe and transferrin receptor 2 (Tfr2) do not interact. PLoS One. 8(10):e77267. doi: 10.1371/journal.pone.0077267. (Pubmed) (PDF)  [↩]
15. Schmidt PJ and Fleming MD. (2012) Transgenic HFE-dependent induction of hepcidin mice does not require transferrin receptor-2.  Am J Hematol. 87(6):588-95. doi: 10.1002/ajh.23173. (Pubmed) (PDF)  [↩]
16. Ali-Rahmani F, Grigson PS, Lee S, Neely E, Connor JR, Schengrund CL. (2013) H63D mutation in hemochromatosis alters cholesterol metabolism and induces memory impairment. Neurobiol Aging. 35(6): 1511.e1-1511.e12. doi: 10.1016/j.neurobiolaging.2013.12.014. (Pubmed) [↩]
17. Piperno A, Girelli D, Nemeth E, Trombini P, Bozzini C, Poggiali E, Phung Y, Ganz T, Camaschella C. (2007) Blunted hepcidin response to oral iron challenge in HFE-related hemochromatosis.Blood. 110:4096-4100. doi: 10.1182/blood-2007-06-096503. (Pubmed) (PDF) [↩]
18. Gao J, Chen J, De Domenico I, Koeller DM, Harding CO, Fleming RE, Koeberl DD, Enns CA. (2010) Hepatocyte-targeted HFE and TFR2 control hepcidin expression in mice. Blood. 115(16):3374-81. doi: 10.1182/blood-2009-09-245209. (Pubmed) (PDF)  [↩]
19. Emanuele D, Tuason I, Edwards QT. (2014) HFE-associated hereditary hemochromatosis: Overview of genetics and clinical implications for nurse practitioners in primary care settings. J Am Assoc Nurse Pract. 26(3):133-22. doi: 10.1002/2327-6924.12106. (Pubmed) (PDF)  [↩]
20. Schmidt PJ and Fleming MD. (2012) Transgenic HFE-dependent induction of hepcidin mice does not require transferrin receptor-2.  Am J Hematol. 87(6):588-95. doi: 10.1002/ajh.23173. (Pubmed) (PDF)  [↩]
21. Leitman SF. (2013) Hemochromatosis: The new blood donor. Hematology. 2013:645-650. doi: 10.1182/asheducation-2013.1.645.(Pubmed) (PDF)  [↩]
22. Wood MJ, Powell LW, Ramm GA. (2008) Environmental and genetic modifiers of the progression to fibrosis and cirrhosis in hemochromatosis. Blood. 111(9):4456-4462. doi: 10.1182/blood-2007-11-122374. (Pubmed) (PDF) [↩]
23. Rochette J, Le Gac G, Lassoued K, Férec C, Robson KJ. (2010) Factors influencing disease phenotype and penetrance in HFE haemochromatosis. Hum Genet. 128:233-248. doi: 10.1007/s00439-010-0852-1. (Pubmed)  [↩]
24. Feder JN, Gnirke A, Thomas W, Tsuchihashi Z, Ruddy DA, Basava A, Dormishian F, Domingo R Jr, Ellis MC, Fullan A, Hinton LM, Jones NL, Kimmel BE,Kronmal GS, Lauer P, Lee VK, Loeb DB, Mapa FA, McClelland E, Meyer NC, Mintier GA, Moeller N, Moore T, Morikang E, Prass CE, Quintana L, Starnes SM, Schatzman RC, Brunke KJ, Drayna DT, Risch NJ, Bacon BR, Wolff RK. (1996). A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet. 13:399-408. doi:10.1038/ng0896-399. (Pubmed)  [↩]
25. Adams PC, Reboussin DM, Barton JC, McLaren CE, Eckfeldt JH, McLaren GD, Dawkins FW, Acton RT, Harris EL, Gordeuk VR, Leiendecker-Foster C,Speechley M, Snively BM, Holup JL, Thomson E, Sholinsky P; Hemochromatosis and Iron Overload Screening (HEIRS) Study Research Investigators.(2005) Hemochromatosis and iron-overload screening in a racially diverse population. N Engl J Med. 352(17):1769-1778. doi: 10.1056/NEJMoa041534. (Pubmed) (PDF) [↩]
26. Leitman SF. (2013) Hemochromatosis: The new blood donor. Hematology. 2013:645-650. doi: 10.1182/asheducation-2013.1.645.(Pubmed) (PDF)  [↩]
27. Rochette J, Le Gac G, Lassoued K, Férec C, Robson KJ. (2010) Factors influencing disease phenotype and penetrance in HFE haemochromatosis. Hum Genet. 128:233-248. doi: 10.1007/s00439-010-0852-1. (Pubmed)  [↩]
28. Moirand R, Adams PC, Bicheler V, Brissot P, Deugnier Y. (1997) Clinical features of genetic hemochromatosis in women compared to men. Ann Intern Med. 127:105-110. doi: 10.7326/0003-4819-127-2-199707150-00002. (Pubmed)  [↩]
29. Leitman SF. (2013) Hemochromatosis: The new blood donor. Hematology. 2013:645-650. doi: 10.1182/asheducation-2013.1.645.(Pubmed) (PDF)  [↩]
30. Adams PC, Jeffrey G, Alanen K, Chakrabarti S, Preshaw R, Howson W, Grant D. (1999) Transplantation of haemochromatosis liver and intestine into a normal recipient.Gut. 45(5):783. doi:10.1136/gut.45.5.783. (Pubmed) (PDF) [↩]
31. Adams PC, Reboussin DM, Barton JC, McLaren CE, Eckfeldt JH, McLaren GD, Dawkins FW, Acton RT, Harris EL, Gordeuk VR, Leiendecker-Foster C,Speechley M, Snively BM, Holup JL, Thomson E, Sholinsky P; Hemochromatosis and Iron Overload Screening (HEIRS) Study Research Investigators.(2005) Hemochromatosis and iron-overload screening in a racially diverse population. N Engl J Med. 352(17):1769-1778. doi: 10.1056/NEJMoa041534. (Pubmed) (PDF) [↩]