Highlights
- •HFE hemochromatosis has become less and less severe over the last 30 years despite older age at diagnosis.
- •Chronic fatigue and distal arthralgias remain the most frequent opening symptoms.
- •Reduced alcohol intake and more overweight patients may explain decreased long-term iron load in hemochromatosis.
- •Tobacco smoking may aggravate iron loading.
Background & Aims
Genetic hemochromatosis is mainly related to the homozygous p.Cys282Tyr (C282Y) mutation
in the HFE gene, which causes hepcidin deficiency. Its low penetrance suggests the involvement
of cofactors that modulate its expression. We aimed to describe the evolution of disease
presentation and of non-genetic factors liable to impact hepcidin production in the
long term.
Methods
Clinical symptoms, markers of iron load, and risk factors according to the year of
diagnosis were recorded over 30 years in a cohort of adult C282Y homozygotes. A total
of 2,050 patients (1,460 probands [804 males and 656 females] and 542 relatives [244
males and 346 females]) were studied.
Results
Over time: (i) the proband-to-relative ratio remained roughly stable; (ii) the gender
ratio tended towards equilibrium among probands; (iii) age at diagnosis did not change
among males and increased among females; (iv) the frequency of diabetes and hepatic
fibrosis steadily decreased while that of chronic fatigue and distal joint symptoms
remained stable; (v) transferrin saturation, serum ferritin and the amount of iron
removed decreased; and (vi) the prevalence of excessive alcohol consumption decreased
while that of patients who were overweight increased. Tobacco smoking was associated
with increased transferrin saturation.
Conclusion
Genetic testing did not alter the age at diagnosis, which contrasts with the dramatic
decrease in iron load in both genders. Tobacco smoking could be involved in the extent
of iron loading. Besides HFE testing, which enables the diagnosis of minor forms of the disease, the reduction
of alcohol consumption and the increased frequency of overweight patients may have
played a role in the decreased long-term iron load, as these factors are likely to
improve hepcidin production.
Lay summary
Genetic hemochromatosis is an inherited disorder that leads to progressive iron overload
in the body. It results in chronic fatigue and in potential liver (cirrhosis), pancreas
(diabetes) and joint (arthritis) damage in adulthood. The present study showed that
tobacco smoking may aggravate iron loading, but that hemochromatosis has become less
and less severe over the last 30 years despite patients being older at diagnosis,
likely because of the protective effects of lower alcohol consumption and of increased
weight in the French population.
Graphical abstract

Graphical Abstract
Keywords
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References
- Haemochromatosis.Lancet. 2016; 388: 706-716
- Iron-overload-related disease in HFE hereditary hemochromatosis.N Engl J Med. 2008; 358: 221-230
- Genome-wide association study identifies TF as a significant modifier gene of iron metabolism in HFE hemochromatosis.J Hepatol. 2015; 62: 664-672
- Exome sequencing in HFE C282Y homozygous men with extreme phenotypes identifies a GNPAT variant associated with severe iron overload.Hepatology. 2015;
- An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group.Hepatology. 1996; 24: 289-293
- Noninvasive prediction of fibrosis in C282Y homozygous hemochromatosis.Gastroenterology. 1998; 115: 929-936
- Redox active plasma iron in C282Y/C282Y hemochromatosis.Blood. 2005; 105: 4527-4531
- The natural history of serum iron indices for HFE C282Y homozygosity associated with hereditary hemochromatosis.Gastroenterology. 2008; 135: 1945-1952
- Decreased cardiovascular and extrahepatic cancer-related mortality in treated patients with mild HFE hemochromatosis.J Hepatol. 2015; 62: 682-689
- Impact of HFE genetic testing on clinical presentation of hereditary hemochromatosis: new epidemiological data.BMC Med Genet. 2005; 6: 24
- Diagnosis of hereditary hemochromatosis in the era of genetic testing.Dig Dis Sci. 2012; 57: 2988-2994
- Hemochromatosis in Italy in the last 30 years: role of genetic and acquired factors.Hepatology. 2010; 51: 501-510
- HFE C282Y/H63D compound heterozygotes are at low risk of hemochromatosis-related morbidity.Hepatology. 2009; 50: 94-101
- Screening for hemochromatosis: recommendation statement.Ann Intern Med. 2006; 145: 204-208
- Idiopathic hemochromatosis. Demonstration of recessive transmission and early detection by family HLA typing.N Engl J Med. 1977; 297: 1017-1021
- Excess alcohol greatly increases the prevalence of cirrhosis in hereditary hemochromatosis.Gastroenterology. 2002; 122: 281-289
- Liver fibrosis in genetic hemochromatosis. Respective roles of iron and non-iron-related factors in 127 homozygous patients.J Hepatol. 1992; 16: 122-127
- Miscellaneous non-inflammatory musculoskeletal conditions. Haemochromatosis: the bone and the joint.Best Pract Res Clin Rheumatol. 2011; 25: 649-664
- Iron-mediated regulation of liver hepcidin expression in rats and mice is abolished by alcohol.Hepatology. 2007; 46: 1979-1985
- Increased adipose tissue expression of hepcidin in severe obesity is independent from diabetes and NASH.Gastroenterology. 2006; 131: 788-796
- Iron: the hard player in diabetes pathophysiology.Acta Physiol (Oxf). 2014; 210: 717-732
- Decreased iron burden in overweight C282Y homozygous women: Putative role of increased hepcidin production.Hepatology. 2013; 57: 1784-1792
- Venesection therapy of insulin resistance-associated hepatic iron overload.J Hepatol. 2001; 35: 344-349
- Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs).J Clin Invest. 2007; 117: 1926-1932
- Non-transferrin bound iron: a key role in iron overload and iron toxicity.BBA. 2012; 1820: 403-410
- The relationship between iron overload, clinical symptoms, and age in 410 patients with genetic hemochromatosis.Hepatology. 1997; 25: 162-166
Article info
Publication history
Published online: September 20, 2018
Accepted:
September 4,
2018
Received in revised form:
August 24,
2018
Received:
May 14,
2018
Identification
Copyright
© 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.