Clinical characteristics of HFE C282Y/H63D compound heterozygotes identified in a specialty practice: key differences from HFE C282Y homozygotes

ABSTRACT

Background

Patients with p.C282Y homozygous (p.C282Y) HFE mutations are more likely to develop hemochromatosis (HC) than p.C282Y/p.H63D compound heterozygotes (p.C282Y/H63D).

Research design and methods

We conducted a retrospective chart review of 90 p.C282Y and 31 p.C282Y/H63D patients at a referral practice to illustrate the differences in the natural history of the disease in these two HC cohorts.

Results

Over a median follow-up of 17 years, p.C282Y had higher mean serum ferritin (1105 mg/dL vs. 534 mg/dL, p = 0.001) and transferrin saturations (75.3% vs. 49.5%, p = 0.001) at diagnosis. p.C282Y underwent more therapeutic phlebotomies (TP) till de-ironing (mean 24 vs. 10), had higher mean mobilized iron stores (4759 mg vs. 1932 mg), and required more annual maintenance TP (1.9/year vs. 1.1/year, p = 0.039). p.C282Y/H63D were more likely to have obesity (45.2% vs. 20.2%, p = 0.007) at diagnosis, with a non-significant trend toward consuming more alcohol. There was no significant difference in the development of HC-related complications between the two cohorts.

Conclusions

p.C282Y have a higher mobilizable iron and require more TP. p.C282Y/H63D likely require additional insults such as obesity or alcohol use to develop elevated ferritin. De-ironing may mitigate the risk of developing HC-related complications.

KEYWORDS:

• Iron overload
• hemochromatosis
• HFE gene mutations
• HFE C282Y/H63D compound heterozygotes
• HFE C282Y homozygotes

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

All authors have substantially contributed to the conception and design of the review article and interpreting the relevant literature, and been involved in writing the review article or revised it for intellectual content. M Singal: Conceptualization, Methodology, Investigation, Data Curation, Writing- Original draft, Writing – Review & Editing. A Mahmoud: Investigation, Data Curation, Formal Analysis, Visualization. P Phatak: Conceptualization, Methodology, Writing – Review & Editing, Supervision.

Ethics approval statement

This study was approved by the institutional review board (IRB) at Rochester General Hospital.

Patient consent statement

Due to the retrospective nature of the study, the IRB approved a waiver of informed consent from the patients. The study analyzed anonymized clinical data of the patients.

Acknowledgments

The study was presented as an oral presentation at BioIron 2023, Darwin, Australia (Aug 31^st, 2023).

Data availability statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Additional information

Funding

This paper was not funded.