In clinically suspected haemochromatosis, it is necessary to determine ferritin levels (>300 ng/l) and the value of transferrin saturation (>45 %). Hyperferritinaemia without elevated transferrin saturation is mostly of inflammatory origin. Combination of transferrin saturation and serum ferritin yields good sensitivity and specificity for haemochromatosis, and increase of both these parameters is an indication for analysis of the HFE gene, including determination of C282Y and H63D mutations. Despite increasing availability of the genetic analysis, it is reasonable, particularly from the economic viewpoint, to follow the mentioned sequence of tests [17]. Type 4 hereditary haemochromatosis exhibiting markedly elevated ferritin levels without a simultaneously increased transferrin saturation occurs only exceptionally. The most probable finding in patients with hereditary haemochromatosis is HFE C282Y homozygosity or simultaneous mutation of C282Y and H63D (compound heterozygote). Better availability of genetic testing for HFE gene mutations has significantly reduced the use of diagnostic liver biopsy to determine the hepatic iron index. In addition to laboratory tests of body iron stores, the extent of iron overload may be assessed by non-invasive MRI examination of the liver. A random finding of a mutation without laboratory signs of iron overload results from low penetrance of the mutation and is not indicated for treatment. Examination of other rare mutations of the HJV and HAMP gene is indicted only in case of a suspected juvenile form of the disease.

Iron deposited in tissues triggers by its toxic action inflammatory changes and gradual destruction of the affected organs. Hepatic fibrosis and cirrhosis (20 % of treated patients) with development of hepatocellular carcinoma and cardiomyopathy (10 % of patients) are late but life-threatening complications of haemochromatosis [11]. As compared to the healthy population, the overall mortality of patients with manifest hereditary haemochromatosis is 2–2.2 times higher [10, 18], the main contributing factors being hepatic cirrhosis (3.4 times higher mortality), hepatocellular carcinoma (0.9 % of patients annually) and cardiomyopathy. Other associated diseases include diabetes mellitus (12–20 % of patients, OR 5.4) and hypogonadism (OR 2.7) that result from destruction of endocrine glands. A typical feature is also bronzing of the skin.

The mentioned complications may be prevented or their manifestation resolved by regular phlebotomies. These mobilise iron from the tissues and eliminate it. Although no randomised studies are available, phlebotomies reduce iron stores down to the lower limit of the physiological reference range in the first phase of the treatment (500 ml of blood twice a week for 1 year) and in the second phase (every 3–4 months for the rest of life) prevent further accumulation of iron in the organism [11]. This approach effectively prevents life-threatening complications and consequently decreases mortality. The advantages of this treatment are its efficacy, simplicity and inexpensiveness. In addition, it has been recognised that patients with hereditary haemochromatosis constitute a safe source of blood for transfusion [19]. A prerequisite for a successful treatment is, however, its early commencement. Alternatively, chelation therapy may be considered. Patients are recommended to avoid the use of high doses of iron preparations and vitamin C.

Clinical features of hereditary haemochromatosis typically include, apart from the already mentioned complications, also arthropathy [20]. Although it is clinically and radiologically similar to osteoarthritis, it is characterised by specific features of the affected joints. The dominant clinical symptoms include pain and symmetrical swelling of second and third metacarpophalangeal (MCP) joints, which occurs in up to 60 % of patients with manifest haemochromatosis and is rare in primary osteoarthritis of hands [21].

Although involvement of other joints of hands is less frequent, polyarthritis of fingers in males should be considered as a warning signal in terms of potential haemochromatosis. However, the incidence of bilateral osteoarthritis of the hip [22] and arthritic changes of knee and ankle joints are frequent. Up to 5 % of patients requiring ankle arthroplasty are diagnosed with haemochromatosis [23]. The most common symptom is thickening of the affected joints (66 %), followed by tenderness (47 %) and swelling (14 %).

Although the symptoms of haemochromatosis arthropathy do not significantly differ from arthritic complaints (mild swelling, pain, stiffness, inability to flex fully MCP joints), some patients report intermittent or acute inflammatory changes of the affected joints with pain and swelling, not unlike in synovitis. These episodes are probably attacks of pseudogout resulting from early calcium pyrophosphate dihydrate (CPPD) crystal deposition (chondrocalcinosis) [24].

The pathophysiology of joint involvement in haemochromatosis remains unclear. A serum ferritin level exceeding 1000 ng/ml at the time of diagnosis is associated with haemochromatosis arthropathy [25, 26] and also with a higher risk of joint failure requiring joint replacement [27]. In 37 % of patients with haemochromatosis, iron deposition was found in synovial resection samples [22]. Although our findings confirm significantly higher haemosiderin deposition in the affected joints of patients with haemochromatosis [28], these findings are not specific for this disease and are common also in other inflammatory rheumatic diseases [29].

As compared to the healthy population, serum ferritin levels are elevated also in males with osteoarthritis of the knee and are associated with a more severe degree of radiological changes [30]. Higher iron levels were detected also in joints affected by osteoarthritis [31], and the heterozygous H63D mutation is more common in patients with primary osteoarthritis of talocrural joints who do not exhibit other manifestations of iron overload [32]. Also, precipitation of CPPD crystals is promoted by iron and thus iron might be directly responsible for the higher occurrence of chondrocalcinosis in patients with haemochromatosis. Therefore, it seems that iron may play a certain role in the development of pathological changes of joints in haemochromatosis, as well as in other arthropathies.

In vitro, iron impairs the synthesis of proteoglycans, induces lipid peroxidation by production of free radicals, thus impairing chondrocyte metabolism, and also negatively affects osteoblasts [33, 34]. In enchondral ossification, an important role is played by hypoxia-inducible factor 2α (HIF2α), the expression of which increases in conditions of elevated iron levels [35]. HIF2α levels are higher in the cartilage of both mice and humans with osteoarthritis, and it is generally known that it induces catabolic enzymes (metalloproteinase, aggrecanase-1, NO-synthetase-2 and cyclooxygenase 2) in chondrocytes [36]. HIF2α could thus serve as a mediator of the adverse effects of iron upon joints.

At tissue level, we have demonstrated that synovial tissue in patients with haemochromatosis resembles by cell infiltrate composition osteoarthritis rather than rheumatoid arthritis [28], except for a significantly increased numberof granulocytes that are more typical of rheumatoid or psoriatic arthritis. At the same time, ferritin is able to induce directly the synthesis of pro-inflammatory cytokine IL1 [37], which damages chondrocytes and osteoblasts. Although the relevance of these findings is not clear yet, they may support the use of targeted therapy blocking mechanisms of innate immunity [38]. The role of adhesive molecules in the pathophysiology of arthropathy is not known, either, but VCAM-1 levels correlated well with the presence and severity of arthropathy in patients with haemochromatosis and may serve as a biomarker in its assessment [39].

At the same time, patients with haemochromatosis often develop osteoporosis which belongs to the clinical spectrum of iron overload manifestations. However, also hepatic cirrhosis and hypogonadism may contribute to the development of osteoporosis.

The first studies dealing with hereditary haemochromatosis arthropathy reported a 50–60 % prevalence of joint symptoms in patients [40]. According to our findings, joint pain is reported by up to 70 % of patients with haemochromatosis (at the age of 56 years) [41]. Arthropathy is thus the most common clinical manifestation of hereditary haemochromatosis. Certain studies have not confirmed an increased incidence of arthropathy (defined as painful MCP2 and MCP3 joints) in patients with hereditary haemochromatosis. However, in our group of patients (n = 199), the dominant manifestation of arthropathy was not pain but swelling of MCP joints [41]. This may explain the absence of an increased occurrence of arthropathy (defined as painful swelling) in some cohorts. The informative value of the studies published so far is limited also by the small number of included homozygotes and the lack of a complete rheumatologic examination of each patient.

It is remarkable that clinical manifestations of arthropathy are not only a frequent but also an early symptom of iron overload [12, 41]. According to our findings, even today they precede the diagnosis of haemochromatosis by more than 6 years. As a result, up to 50 % of patients exhibit manifestations of arthropathy at the time when they are diagnosed with haemochromatosis, and its treatment is started. Thus, correct interpretation of clinical symptoms, radiological changes and laboratory parameters may contribute to earlier diagnosis of the underlying disease and a timely prevention of other potentially life-threatening complications of haemochromatosis.

Similarly as in osteoarthritis, radiological changes in haemochromatosis arthropathy include narrowing of the joint space, formation of osteophytes, development of cysts and erosive changes [42], as well as sclerotic changes and deformity of the joint [43] (Fig. 14.1). It is characterised by beak-like osteophytes located on the radial aspect of MCP joints. In our group of 170 patients, the most common radiological findings were osteophytes in MCP2 and MCP3 joints (45 %) and narrowing of joint space (48 %) followed by erosive changes (28 %). Using a validated score specific for haemochromatosis arthropathy, we have confirmed the general clinical finding that arthropathy involves most frequently MCP2 and MCP3 joints [43] (Fig. 14.2). At the same time, we have found, in agreement with clinical data published in other studies [23], that radiological changes are not confined only to MCP joints, but are relatively frequent and severe also in other joints (talocrural, radiocarpal). Unlike other authors, we have not found more severe involvement of the dominant right hand [43] (Fig. 14.2). Chondrocalcinosis is identified in 11–33 % of patients, most often in the knee and radiocarpal joints [24] (Fig. 14.3). Some studies also report the relatively rare occurrence of femoral head necrosis in patients with haemochromatosis.

Most important, in terms of rheumatology, is the fact that involvement of joints, although not affecting patients’ survival, has by far the worst prognosis as to the patients’ quality of life and the possibility of its reversal by phlebotomy treatment. More than 60 % of patients in our cohort were unsatisfied or highly unsatisfied with the condition of their joints, and only 15 % of them reported resolution of joint complaints after commencement of phlebotomy therapy [41]. In the remaining patients, the joint complaints remained the same, and in 16 % of them, the disease progressed further despite treatment [41]. This correlates with the results of other studies showing that arthropathy is the only complication associated with haemochromatosis that is unresponsive to causal treatment [44].