Homozygous C282Y Hereditary Hemochromatosis: Evolution and Prognosis in a Cohort of Patients Followed up over 30 Years

INTRODUCTION

Hereditary hemochromatosis (HH) is caused by increased intestinal absorption with subsequent deposition in tissues. Eventually, this may result in hepatic cirrhosis (HC), hepatocellular carcinoma (HCC), endocrine dysfunction, arthropathy, and cardiomyopathy. Most patients are homozygous for the C282Y mutation in the HFE gene, with a minority bearing mutations in other genes. Despite many studies on the epidemiology of HH, its current impact on life expectancy and the presenting factors determining prognosis in homozygous C282Y patients remain poorly defined.

OBJECTIVE

This study aims to characterize the evolution, impact on life expectancy, and initial prognostic factors in a modern series of patients with homozygous C282Y HH, homogeneously managed and closely followed up by the same medical team over three decades.

METHODS

We retrospectively reviewed the clinical records of individuals diagnosed with HH and treated by phlebotomy or erythrocytapheresis at our hospital from January 1990 to June 2024. HH was diagnosed based on specific genetic abnormalities (C282Y/C282Y), transferrin saturation >45%, and serum ferritin >200 µg/l.

RESULTS

A total of 125 consecutive patients were included in the study. The median age at diagnosis was 49 years (interquartile range [IQR]: 40-59), and 98 patients (78.4%) were males. In 91 (72.8%) individuals, HH diagnosis was triggered by the incidental finding of abnormal laboratory results, including routine analysis, investigation of symptoms unrelated to HH, or family studies. At diagnosis, 37 patients (29.6%) had some complications of HH: arthralgia in 23 patients, insulin-dependent diabetes mellitus (IDDM) in 4, HC in 4 (2 with superimposed HCC), and dilated cardiomyopathy in one.

The median and IQR of serum ferritin and transferrin saturation were 1071 µg/l (676–1518) and transferrin saturation 81% (66-97), respectively. Ferritin levels were significantly lower in patients diagnosed incidentally (p=0.02), those without complications at baseline (p< 0.01), and in women (p<0.01). Ferritin levels were especially high (median 3450 µg/l, IQR: 1865 – 5756) in patients with more advanced initial complications: HC, HCC and cardiomyopathy.

After a median follow-up of 18 years (IQR: 10.1 – 24.3), 26 patients had died, and 99 were alive at the study’s closing date (June 2024). The overall projected survival at 20 years was 81% (CI 95%: 72%-88%). The ultimate causes of death were malignancies (9 patients), cardiac failure (n=4), infection (n=4), HC (n=2), and others (n=7). Initial factors independently associated with increased mortality were age (HR: 1.06, 95% CI: 1.02-1.10 per year, p=0.002) and ferritin > 1000 µg/l (HR: 10.13, 95% CI: 1.33-76.9, p=0.027).

One or more complications not initially present were diagnosed in 33 patients after a median follow-up of 13 years, including HCC in 11 patients (without prior recognized CH in 4). A total of 18 other malignancies were diagnosed in 16 patients (13 solid organ carcinomas, 5 hematological neoplasms). The patients with non-HCC malignancies were more likely to have had initial ferritin levels >1000 µg/l than the remaining patients (94% and 50%, respectively, p<0.01). Life expectancy of patients was not significantly different from the general population matched by age, sex, and year of diagnosis.

CONCLUSIONS

Homozygous C282Y HH does not reduce life expectancy in patients managed and closely followed up according to current standards. The late appearance of HCC, even among non-cirrhotic individuals, stresses the need for lifelong surveillance. Early diagnosis should be encouraged to avoid complications secondary to iron accumulation and, perhaps, the incidence of associated neoplasms.