Introduction

HFE hemochromatosis (HH) is a systemic disorder leading to iron overload in parenchymatous organs, eventually causing organ failure. Clinically manifest HH is associated with high morbidity and increased mortality. The classical triad was characterized by liver cirrhosis, diabetes and skin hyperpigmentation. The majority of symptomatic patients harbor a homozygous mutation leading to a cysteine-to-tyrosine substitution at amino acid position 282 (C282Y) in the High Iron Fe (HFE) gene on chromosome 6, which leads to inappropiate increased iron absorption from the gut [1]. The homozygous prevalence of this autosomal-recessive mutation is ~0.5% in Western Europe [2]. Other mutations such as the H63D mutation (histidine to aspartic acid) of the HFE gene can also be found frequently, but are usually clinically not relevant [3].

Phenotypic expression of C282Y homozygosity is variable and depends on environmental and host factors [4] and polymorphisms of TMPRSS6, GNPAT and PCSK7 genes relevant to iron absorption and cirrhosis risk [5, 6]. The rate of iron-overload-related disease in C282Y homozygotes was 28.4% for men and 1.2% for women in a large epidemiological study [7]. Joint pain often presents first and is the most common manifestation of HH. While symptoms do not differ from primary osteoarthritis (OA), the typical distribution of affected joints found in HH is remarkable. Metacarpophalangeal and ankle joints are frequently affected in HH, while hip joints are regularly involved in both disorders [8]. Site-specific arthropathy may be influenced by iron overload in HH patients. Arthropathy in HH was associated with iron overload in some studies [9], but not in others [10]. However, HH individuals seem to develop hip joint arthropathy earlier in life than patients with primary OA [11]. Therefore, we hypothesized that screening younger patients with severe OA of the hip could identify HH patients.

Patients and methods

Results

Mean age of 940 patients undergoing hip replacement surgery was 59.4 ± 9.5 years and ranged from 19 to 70 years. Male to female ratio of patients enrolled in the study was 1:1.4 and women were 1.7 years older in average. With a mean BMI of 27.9 ± 5.1, in overall patients could be classified pre-obese according to the World Health Organization. Mean BMI in the control group was 27.0 ± 4.8 (Table 1).

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Table 1. Iron status and HFE genotype in patients with severe ostearthritis of the hip (OA) and controls.

https://doi.org/10.1371/journal.pone.0207415.t001

Serum ferritin and transferrin saturation levels were significantly higher in the control than in the patient group. C282Y homozygosity was found in only one (0.1%) out of 940 patients with end-stage OA of the hip. In the control group, six (0.6%) cases of C282Y homozygosity were identified. Compound heterozygosity (C282Y/H63D) was found in 10 (1.1%) versus 22 (2.4) of 940 individuals in the patient versus control cohort, respectively. Thus, C282Y homozygous and compound heterozygous mutations were significantly less prevalent in the hip OA group (p<0.05). According to this, multivariate regression analyses revealed a significantly lower prevalence of compound heterozygosity (C282Y/H63D) in OA patients than in controls (OR 0.44, 95%-CI 0.20–0.97, p<0.05). Prevalence of heterozygous C282Y and H63D mutations was 63 (6.7%) versus 82 (8.8%) and 203 (21.6%) versus 182 (19.6%) in the patient and control population, respectively. An equal number of 13 (1.4%) homozygous H63D mutations were found in both groups (Table 1 and Fig 1). HFE genotype was not available for 11 of 940 controls.

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Fig 1. Prevalence of HFE genotype in patients with severe osteoarthritis of the hip (OA) and controls.

https://doi.org/10.1371/journal.pone.0207415.g001

Discussion

Tissue iron accumulation in HH can lead to major complications such as liver cirrhosis and hepatocellular carcinoma. Iron depletion by phlebotomy is the treatment of choice with potential reversal of hepatic fibrosis [13]. Thus, early diagnosis of the disease to prevent complications is important and screening of at-risk populations warranted. In this regard, a case finding approach by targeted screening of vulnerable individuals with signs suggestive of iron overload, as well as offering testing to Caucasian men of Northern European ancestry, has been discussed [14].

Joint pain is the most frequent presentation in patients with HH and iron overload and often precedes other symptoms [8]. In contrast to primary OA, HH arthropathy frequently affects men and shows symmetric joint involvement. Symptoms of the typically affected second and third metacarpophalangeal joints may be subtle and do not necessarily lead patients to consult rheumatologists. Bilateral ankle joint involvement is also typical in HH, but its prevalence in patients is quite low [15]. Other affected joint regions include the wrists, as well as knee and hip joints. Importantly, HH was established as a risk factor for hip replacement at younger age [11]. An increased risk of musculoskeletal complications was confirmed in two independent population-based studies in Sweden and Australia [16, 17].

As an approach for screening of at-risk populations, we analyzed serum iron status and HFE genotypes in patients with end-stage hip OA under the age of 70. Given the previous findings from epidemiological studies, we estimated a three-fold increase in C282Y homozygous mutations in our patient cohort compared to the general population. Nevertheless, our data did not reveal a significant increase in HFE mutations nor laboratory signs of iron overload in our study population compared to age- and sex-matched individuals. In fact, C282Y homozygosity was even lower in prevalence than in the control population, the latter being in the expected range. Thus, our study does not suggest a benefit from HFE screening in younger patients with severe OA of the hip. A possible reason for not detecting an increase in C282Y homozygotes in the OA group is that subjects in our study were not primarily selected by iron overload and few suffered from elevated serum ferritin and transferrin saturation levels. Further, it cannot be excluded that hemochromatosis patients with joint pain are being diagnosed and treated at earlier stages in Austria. In fact, many rheumatologists include full iron status in their diagnostic work-up of newly presenting patients. Also, a referral bias of certain patient groups cannot be fully excluded, although all recruiting centers are part of the social insurance system.

Hence, other case identification approaches have to be developed and tested in HH. Regarding hemochromatosis arthropathy, although rare, patients with severe ankle OA without mechanical trigger factors may serve as potential candidates. Although we could not prove a benefit in testing patients with severe hip OA for HH, studies for screening of at-risk populations need to be continued in order to prevent the course of this potentially life-limiting disease by its early detection and therapy.

Acknowledgments

The authors would like to thank Franz Varga, Monika Rumpler and Silvia Spitzer for support, statistical and technical assistance.