Don't Forget About Hemochromatosis, With Paul Thompson, MD


Paul D. Thompson, MD, pens a column underlining the prevalence and impact of hemochromatosis on the health of patients based on current evidence.

Paul D. Thompson, MD

Paul D. Thompson, MD

Hemochromatosis is caused by defects in the hemostatic iron regulator (HFE) gene (HFE).1 HFE binds to the transferrin receptor 2 (TRF-2). TRF-2 increases hepcidin production. Hepcidin inhibits elemental iron (Fe) uptake by binding to and downregulating the Fe exporter, ferroportin, which transports Fe from and between cells. So, genetic defects in HFE, decrease HFE binding to TRF-2, decreasing hepcidin production, increasing ferroportin, and increasing Fe transport from the gut.

The most common gene mutation for hemochromatosis, HFE C282Y, probably originated in a single Celt or Viking in Northwestern Europe approximately 6000 years ago.2 It probably conveyed some survival advantage such as height2, exercise performance1, and resistance to certain infections.3 Swiss men and women homozygous for the C282Y mutation average 4.3 and 3.3 cm taller, respectively, than a reference Swiss population.2

Competitive athletes carrying HFE variants demonstrate increased exercise performance and were 8% faster on a 10 km cycling time trial and had a 17% higher maximal oxygen uptake.1 The gene is highly prevalent in individuals of northern European origin and more than 6% of whites have at least one HFE variant.4

Ireland has the highest prevalence by country.2 Despite this prevalence, only 28% of homozygous men and 1.4% of homozygous women develop symptoms of hemochromatosis.4

That’s because women lose iron with menstruation so present later in life, if at all. Also, alcohol enhances iron absorption and thereby affects the age of presentation. Hemochromatosis can present in mid-life with unexplained fatigue, joint pain, liver disease, diabetes, impotence due to hypogonadotrophic hypogonadism, bronzing of the skin (“bronze diabetes”)5, hypothyroidism, and arthritis.4,6

Clinicians should consider the possibility of hemochromatosis in multiple disease states because of its prevalence in Northern Europeans and its effect on many organ systems. This is especially true for cardiologists because it can produce both dilated and restrictive cardiomyopathy, angina without CAD, pericarditis, atrial fibrillation, and more rarely, ventricular arrhythmias.4 Serum iron, transferrin saturation, and ferritin levels are usually all elevated. Genetic testing is recommended when the transferrin saturation value exceeds 45%.6

Cardiac involvement is determined by cMRI with T2 imaging. The usual treatment is phlebotomy, but chelation therapy can be used for severe iron infiltration of the liver or heart because phlebotomy takes time to be effective.4 Both the hepatic and cardiac infiltration are reversible so clinicians and cardiologists should think of the disease because of its prevalence and its multiple systemic and cardiac manifestations.


  1. Thakkar D, et. Al. HFE Genotype and Endurance Performance in Competitive Male Athletes. Med Sci Sports Exerc. 2021 Jul 1;53(7):1385-1390. PMID: 33433155
  2. Cippa PE, Krayenbuehl P-A. Increased height in HFE hemochromatosis. N Engl J. 2013 Aug 22;369(8):785-6. PMID: 23964954.
  3. Stefanova, D, Endogenous hepcidin and its agonist mediate resistance to selected infections by clearing non-transferrin-bound iron. Blood. 2017 Jul 20;130(3):245-257. PMID: 28465342
  4. Moore, AB Case 25-2021: A 48-Year-Old Man with Fatigue and Leg Swelling. N Engl J Med. 2021 Aug 19;385(8):745-754. PMID: 34407347
  5. Porter JL, Rawla P.2021 Jun 15. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan. PMID: 28613612
  6. Pietrangelo, A. Hereditary hemochromatosis--a new look at an old disease. Engl J Med. 2004 Jun 3;350(23):2383-97. PMID: 15175440
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