Version July 2025
INTRODUCTION —
Arthritis is a common manifestation of hereditary hemochromatosis (HH), also called genetic hemochromatosis. HH is a genetically determined disorder in which mutations in the HFE gene, or less frequently the transferrin receptor 2 (TFR2) gene or other genes, cause increased intestinal iron absorption. (See "HFE and other hemochromatosis genes".)
The resulting clinical manifestations of this disorder (and of other forms of iron overload) are related to the iron deposition in organs, such as the liver, pancreas, heart, and pituitary, and in the cartilage and synovial tissues of the joints. Other major clinical manifestations of iron accumulation include liver disease, skin pigmentation, diabetes mellitus, impotence in males, and cardiac enlargement with or without heart failure or conduction defects (table 1). (See "Clinical manifestations and diagnosis of hereditary hemochromatosis".)
This topic reviews the major musculoskeletal manifestations of hemochromatosis, including arthropathy and osteoporosis, and their pathogenesis, diagnosis, and management. Screening for HH and the major genetic, clinical, diagnostic, and therapeutic features of hereditary hemochromatosis are discussed separately:
●(See "HFE and other hemochromatosis genes".)
●(See "Gene test interpretation: HFE (hereditary hemochromatosis gene)".)
●(See "Clinical manifestations and diagnosis of hereditary hemochromatosis".)
●(See "Management and prognosis of hereditary hemochromatosis".)
PATHOGENESIS —
Iron deposition and defects in cartilage and in immunologic function have been implicated as factors that contribute to the development of arthritis in hereditary hemochromatosis (HH). HFE gene analysis is useful in understanding the clinical manifestations of HH and patient management. However, the precise mechanisms underlying the arthritis among patients with HH are unknown. (See 'Iron deposition' below and 'Cartilage defect' below and 'Immunologic defects' below.)
Genetic factors — Joint involvement is more common in some genetic forms of HH than others, and the first comprehensive analysis comparing the different phenotypic and clinical aspects of the genetic forms of HH suggests that factors other than iron overload may be contributing to joint pathology in patients with HFE HH [1]. HH and its phenotypic variability have been well studied, but less is known about the natural history of non-HFE HH caused by mutations in the HJV, HAMP, or TFR2 genes. Analyses in this study, which compared the phenotypic and clinical presentations of hepcidin-deficient forms of HH, indicated that non-HFE forms of HH have an earlier age of onset and a more severe clinical course than HFE HH; all clinical outcomes analyzed were more prevalent in the juvenile forms of HH, with the exception of arthritis and arthropathy, which were more commonly seen in HFE HH. HJV and HAMP HH were phenotypically and clinically very similar and had the most severe presentation, with cardiomyopathy and hypogonadism being particularly prevalent findings. TFR2 HH was more intermediate in its age of onset and severity.
HFE mutations were assessed in 31,192 persons of northern European ancestry who were followed for an average of 12 years [2]. C282Y is the HFE allele most commonly associated with HH. The proportion of HFE C282Y homozygotes with documented iron overload-related disease was 28.4 percent in males and 1.2 percent in females. Male C282Y homozygotes with a serum ferritin level of 1000 mg/L or more were more likely to report fatigue, use of arthritis medicines, and a history of liver disease.
In another study, the overall prevalence of self-reported osteoarthritis (OA) among 306 patients with HH was higher with C282Y homozygosity than compound heterozygosity (53.4 versus 32.5 percent) [3]. Indeed, HH is a risk factor for joint replacement surgery for severe secondary OA [4,5].
Heterozygosity for the C282Y mutation is common (6 to 20 percent), but individuals who are heterozygous have not been found to be at increased risk of arthritis. In a study of 3531 patients with HH and 11,794 of their first-degree relatives, who were assumed to be heterozygous for the C282Y mutation, patients with HH, but not their relatives, were at increased risk of arthritis and of need for joint replacement surgery [6]. Similarly, a study of 1372 individuals has demonstrated that heterozygosity for the C282Y or H63D mutations of the HFE gene was not a risk factor for arthritis in populations of British Isles descent [7]. However, possession of either C282Y or H63D mutations in the HFE gene is associated with primary OA in the joints commonly affected in hemochromatotic arthropathy [8].
More information on genetic factors in hemochromatosis is provided separately. (See "HFE and other hemochromatosis genes".)
Iron deposition — Evidence for a role of iron deposition in the pathogenesis of HH is mixed; some findings support such a role, while others do not. The development of arthritis in hereditary hemochromatosis (HH) cannot be predicted by the level of serum iron or by other measures of iron overload [9]. Although high serum transferrin saturation values correspond with the presence of arthritis, a high value may only represent an extended duration of disease [10].
Iron deposition within joints may trigger a number of pathologic events, such as free radical generation and crystal deposition. In some cases, the generation of free radicals may cause changes in immunoglobulin carbohydrate composition that promote immune complex formation and inflammation [11-15]. These alterations are superimposed upon joint changes that result from calcium pyrophosphate (CPP) crystal deposition.
The presence of ferric salts within joints may enhance crystal deposition by promoting crystal formation and by inhibiting crystal removal [16,17]. As an example, the clearance rate of CPP crystals from joints was measured in a rabbit model of iron deposition [18]; synovial hemosiderosis due to the injection of blood into the knee significantly reduced the clearance of CPP crystals, suggesting that intracellular pyrophosphatases are inhibited by iron.
Additional evidence of the role of iron was shown in a study in which arthropathy was found in 24 percent (10 of 41) of patients with definite/probable HH [19]. The association observed between this arthropathy, homozygosity for C282Y, and serum ferritin concentrations at the time of diagnosis suggests that iron load is likely to be a major determinant of arthropathy in HH and to be more important than occupational factors. Arthropathy in definite/probable HH was more common with increasing age and was associated with ferritin concentrations >1000 mcg/L at the time of diagnosis (odds ratio 150.89).
Further support for localized iron overload having a role in the arthritis of HH came from a study of synovial fluid ferritin concentrations in patients with knee OA who underwent HFE genotyping [20]. Concentrations of ferritin in the synovial fluid were found to be two- to threefold higher in knee OA patients with HFE gene mutations compared with wild-type patients with OA.
In contrast to the evidence supporting an important role for iron deposition in causing arthritis in HH, a number of other observations argue against the singularity of this role:
●The removal of systemic iron has little effect upon arthritic symptoms [21].
●The arthritis of HH may not be specific for iron overload [22]. Although increased deposition of iron in the synovial tissue is observed in a variety of other diseases, including rheumatoid arthritis (RA) [13,22], degenerative arthritis [11], tenosynovial giant cell tumor (formerly known as pigmented villonodular synovitis) [13,23], hemophilia [24], and hemarthrosis [25], the pathologic findings in the joints of patients with these disorders differ from those observed in HH (see 'Joint pathology' below). In addition, the arthropathy in HH is clinically similar to that observed in diseases not associated with iron deposition, including calcium pyrophosphate crystal deposition (CPPD) disease [26-29]. (See 'Clinical features' below.)
Cartilage defect — An additional metabolic abnormality, independent of the disorder of iron metabolism, may be responsible for an alteration in cartilage matrix among patients with HH, thereby causing arthritis [30,31]. This mechanism is consistent with the observation that the arthritis of HH is clinically similar to that of other metabolic disorders, such as hyperparathyroidism, ochronosis, and Wilson's disease [32].
Increased levels of fragments of parathyroid hormone (PTH) occur in HH and may play a role in the osteoarticular manifestations of the disease [33]. However, similarly elevated levels of PTH fragments occur in CPPD disease in the absence of HH [34]. This suggests that the two disorders may share some pathophysiologic mechanisms, in addition to chondrocalcinosis.
Immunologic defects — Abnormalities in immune cell function may also contribute to the development of arthritis in HH. A variety of immunologic abnormalities have been observed among patients with secondary iron overload and parenteral iron overload, but it is unclear whether such dysfunction is primary or results from the effects of immune-modifying treatments, such as blood transfusions and splenectomy [35]. Reported abnormalities include a decrease in superoxide anion production from neutrophils [35,36], a reduction in CD4, and both expansion of and decrease in CD8-positive T cells [37-40].
Cytotoxic CD8+ T-cells show reduced activity [41] and use a skewed T-cell receptor repertoire [42]. It is not clear whether these changes are due to the altered HFE protein or to other pathological changes of HH.
JOINT PATHOLOGY —
Synovial tissue in hereditary hemochromatosis (HH) is brown because of iron deposition [22,31], and abnormal amounts of iron deposits, little or no signs of synovial inflammation, and calcium pyrophosphate crystal deposition (CPPD) are characteristic microscopic examination findings. Synovial histology in HH arthropathy resembles osteoarthritis (OA). However, neutrophil invasion is significantly increased, especially in joints with iron deposition, and may stimulate the production of matrix enzymes, causing cartilage degradation and rapidly progressive articular damage [43]. Other common findings include:
●The histological picture of the synovium in HH arthropathy largely resembles a process reminiscent of OA. However, in a study of synovial tissue obtained during surgery from 15 patients with HH, 20 with rheumatoid arthritis (RA), and 39 with OA, neutrophil invasion was markedly increased in tissues from HH arthropathy, especially in joints with iron deposition [43]. Accumulation of neutrophils may be crucial for the production of matrix enzymes, which enables cartilage degradation and more rapidly progressive articular damage.
●The intimal and phagocytic cells may contain iron in association with intimal cell hyperplasia and villus formation [44].
●Cartilage may be stripped from the subchondral bone at the level of the tidemark in the calcified cartilage zone. This finding, which may be specific to HH, is caused by increased susceptibility to shearing forces at the bone cartilage interface (picture 1) [26].
●Apatite and calcium pyrophosphate (CPP) crystals may occur together with iron deposits [12], but there is no spatial relationship. In addition, crystals can be found in the absence of iron deposits. CPP crystals in intervertebral discs are found in the outer and peripheral layers of the annulus fibrosis and of the ligamentum flavum and in association with microfissure formation [45].
Chronic inflammatory cell infiltration is uncommon. Electron microscopy reveals that iron is predominantly found in the lining of cells rich in rough endoplasmic reticulum.
CLINICAL FEATURES
Prevalence and demographics — Approximately one-half of patients with hereditary hemochromatosis (HH), if untreated, eventually develop arthritis [21,46]. Symptoms are more severe in those over 50 years of age [21,47]. Joint involvement has not been mentioned in reports of juvenile-onset HH [48-50].
Clinical manifestations — Arthritis is a frequent, early, and severe symptom of hemochromatosis. Disease is not confined to involvement of the metacarpophalangeal (MCP) joints and can lead to severe damage requiring joint replacement [51]. The arthritic manifestations of HH are diverse [51,52]:
●Onset of symptoms – While arthritis may be the presenting symptom of HH [53,54], rheumatic symptoms can occur after the diagnosis has been made.
●Common clinical symptoms – The most common presenting symptom is twinges of pain upon flexing the small joints of the hand, particularly the second and third MCP joints. Joint inflammation is typically minimal [21,55]. Arthritis may then progress to involve the large joints, particularly the hips, knees, and shoulders; such involvement sometimes causes severe disability, requiring surgery [26]. In a cohort of patients with HH that included 16 patients with related arthritis, the most common sites of involvement were the wrists and MCP joints, and severe involvement of the hip occurred in six patients [56].
While most patients with HH arthropathy are symptomatic, some patients have only mild arthralgia at night or upon awakening [31]. Asymptomatic joint involvement has also been demonstrated by ultrasonography in some patients [57].
Bony swelling may develop and may superficially resemble osteoarthritis (OA). Features that help distinguish HH arthropathy from OA are described below. (See 'Differential diagnosis' below.)
●Flares of acute synovitis – Patients with HH arthritis can have acute flares of synovitis, although it is challenging to know whether this might represent superimposed acute calcium pyrophosphate (CPP) crystal arthritis [21,47,58]. The distribution of joint involvement may resemble rheumatoid arthritis (RA) [59]. Acute attacks of inflammation with bilateral destruction of the MCP joints can occur, and reduced flexion at the MCP joints has been noted. Features that help distinguish arthritis related to hemochromatosis from calcium pyrophosphate crystal deposition (CPPD) disease and rheumatoid arthritis (RA) are described below. (See 'Differential diagnosis' below.)
Laboratory findings — Patients with inflammatory joint findings may exhibit elevated acute phase reactants, but other laboratory abnormalities will reflect the iron overload and related organ involvement. These findings and HFE gene testing are described in detail separately. (See "Clinical manifestations and diagnosis of hereditary hemochromatosis".)
Imaging — Arthritis among patients with HH is characterized by the following patterns of radiographic involvement [26,60]:
●Chondrocalcinosis (which refers to radiographic calcification in hyaline and/or fibrocartilage) is common and is usually asymptomatic. (See 'Cartilage calcification (chondrocalcinosis)' below.)
●Hypertrophic OA with abundant osteophytosis and sclerosis.
●Disease specific changes which include subchondral radiolucency of the femoral head (image 1), hook-like osteophytes on the metacarpal heads, and a degenerative predilection for the MCP joint rather than the scapholunate.
Small cysts or erosions of approximately 1 to 3 mm in diameter affecting the metacarpal heads may be observed early in the course of the disease [21,47]. In addition, joint surfaces may become roughened and irregular, thereby resulting in the destruction of the articular surface (image 2A-B) [31]. Radiographic evidence of sclerosis and joint space narrowing may also be observed.
●Magnetic resonance imaging (MRI) can demonstrate the presence of inflammatory arthritis with erosions and cyst formation. The presence of intraarticular iron deposition has also been seen [61,62].
Subclinical joint disease can be shown by ultrasonography in some patients. Ultrasound examination of 64 joints in 24 HH patents without arthritis showed evidence of ongoing subclinical inflammation and cartilage damage with erosions, though to a lesser degree than in patients with HH arthritis [57].
A feasible and reliable radiologic assessment tool for the evaluation of hemochromatosis arthropathy in the MCPs and wrists has been validated, and an atlas of characteristic radiographic features has been provided [63].
Associated conditions — Several conditions appear to occur with increased frequency in patients with HH, including chondrocalcinosis and osteoporosis. In a study of 25,157 United States veterans with CPPD disease, HH was one of the five disorders with the strongest positive association with CPPD disease [64]. (See 'Cartilage calcification (chondrocalcinosis)' below and 'Osteoporosis and osteoarthritis' below.)
Cartilage calcification (chondrocalcinosis) — Cartilage calcification (chondrocalcinosis) due to CPP crystal deposition is present in approximately two-thirds of patients with HH [21]. As the disorder progresses, the incidence and severity of CPP crystal deposition increases. The knees and wrists are most frequently involved, while the hips, symphysis pubis, and spine may also be affected (image 3). Calcification of the intervertebral discs may radiographically resemble ankylosing spondylitis [45]. In addition, the Achilles tendon and plantar fascia may be other sites of soft tissue calcification. (See "Calcium pyrophosphate crystal deposition (CPPD) disease: Clinical manifestations and diagnosis", section on 'Clinical manifestations' and "Calcium pyrophosphate crystal deposition (CPPD) disease: Clinical manifestations and diagnosis", section on 'Imaging findings'.)
Cartilage calcification is not related to age or to the amount of iron deposited. Radiologic progression of chondrocalcinosis (and arthritis) does not decrease or disappear with treatment [55].
There are relatively distinct radiographic differences between the arthropathy of HH and primary CPPD [60]. HH is distinguished by the following:
●More prevalent narrowing of the MCP joints, including those in the fourth and fifth digits
●Peculiar hook-like osteophytes on the radial aspect of the metacarpal heads
●Less prevalent separation of the scaphoid and the lunate bones
These radiographic differences indicate that the arthropathy of HH is related to other factors in addition to the presence of CPPD.
Some patients with radiographic evidence of CPPD develop various clinical symptoms. Features that help distinguish CPPD disease from HH arthritis are described below (see 'Differential diagnosis' below). More information the pathogenesis and typical imaging findings in CPPD disease is provided elsewhere. (See "Pathogenesis and etiology of calcium pyrophosphate crystal deposition (CPPD) disease" and "Calcium pyrophosphate crystal deposition (CPPD) disease: Clinical manifestations and diagnosis", section on 'Imaging findings'.)
Osteoporosis and osteoarthritis — In addition to the arthropathy, a significant decrease in bone density is frequently observed among patients with HH and other forms of iron overload, particularly those with concurrent hypogonadism [31,65-67]. The incidence of osteoporosis varies from 25 to about 50 percent in HH [30,31,47,65,68]. In addition, OA frequently cooccurs with HH. The following studies highlight the relationship between HH, osteoporosis, and OA:
●The relationship of HH to both osteoporosis and OA was evaluated in a study in which a self-administered questionnaire was completed by 306 patients with HH and 304 age- and sex-matched unaffected controls [68]. Osteoporosis was significantly more common in the patients with HH (23.3 versus 4.6 percent). Patients with HH showed trends towards increases in the prevalence of wrist and vertebral fractures, but these trends did not achieve statistical significance. The severity of iron overload, defined by a ferritin level >1000 mcg/L at diagnosis, was statistically significantly associated with osteoporosis, OA, the presence of a hip prosthesis, wrist fractures, and vertebral fractures.
●A case-control study also strongly suggested an increased prevalence of both osteoporosis and OA in patients with HH compared with controls (51 versus 29 percent, adjusted odds ratio [OR] 2.5, 95% CI 1.8-3.6; and 23 versus 5 percent, adjusted OR 7.3, 95% CI 3.2-17.0, respectively) [68]. Among patients with HH, findings of osteoporosis, OA, a hip prosthesis, and wrist and vertebral fractures were more likely in those with more severe iron overload (>1000 mcg/L at time of diagnosis).
●In a study involving patients with HH (n = 10), cortical volumetric bone mineral density and cortical thickness were both reduced, while trabecular microstructure and volumetric bone mineral density were maintained, based upon comparison with age- and sex-matched reference values [69]. The occurrence of bone complications was age dependent; while younger patients presented with osteonecrosis or transient bone marrow edema, patients older than 65 years presented with fractures. High-resolution peripheral quantitative computed tomography (HR-pQCT) was a useful complement to fracture risk assessment to determine microstructural deterioration and volumetric bone mineralization deficits [69].
Osteoporosis is usually clinically asymptomatic and may be localized to the hands. Bone mass is lower in patients with hypogonadism, but osteoporosis can also be seen in eugonadal subjects, indicating that other factors also must contribute [65].
There was significant bone loss in HFE gene-related hemochromatosis in the absence of hypogonadism or cirrhosis [70].
Calcium kinetic studies suggest a deficiency in calcium absorption [31]. Serum concentrations of calcium, phosphorus, and alkaline phosphatase are usually normal. Osteoblastic function is significantly greater in phlebotomized than in non-phlebotomized patients, although the trabecular bone volumes of these two groups were similar in one report [65].
DIAGNOSIS —
Arthritis due to hereditary hemochromatosis (HH) is diagnosed in patients with characteristic joint changes (see 'Clinical features' above) and documented HH. Arthritis is likely to be present and severe in patients with HH; it should be sought and not overlooked. Patients with typical joint findings, such as moderate or severe arthritis of the metacarpophalangeal (MCP) joints or cartilage calcification (chondrocalcinosis), should be evaluated for evidence of iron overload if HH has not previously been considered; such patients should undergo measurement of the transferrin saturation and serum ferritin concentration, which are increased in patients with HH. Imaging of affected joints should be obtained to help confirm the diagnosis, which may be evident radiographically. (See 'Imaging' above.)
Other studies relevant to the diagnosis of HH should be obtained, depending upon the prior evaluation; these include HFE genotyping, which can establish the diagnosis of HH, and may include liver biopsy. The evaluation of the patient with suspected iron overload and the diagnosis of HH are described in detail separately (algorithm 1). (See "Approach to the patient with suspected iron overload" and "Clinical manifestations and diagnosis of hereditary hemochromatosis".)
Determination of the HFE genotype is clinically useful in patients with arthritis of unknown origin to allow early diagnosis of hemochromatosis [71]. HFE gene discovery has simplified the diagnosis of HH and has modified our understanding of clinical presentation and epidemiology [72].
DIFFERENTIAL DIAGNOSIS —
In general, the differential diagnosis includes any cause of an inflammatory arthropathy (see "Evaluation of the adult with polyarticular pain" and "Diagnosis and differential diagnosis of rheumatoid arthritis", section on 'Differential diagnosis'). However, most commonly, the principal arthritic disorders which must be distinguished from the arthropathy of HH are primary calcium pyrophosphate crystal deposition (CPPD) disease and rheumatoid arthritis (RA), the common feature being an inflammatory, progressive erosive arthropathy. Key features of HH arthropathy, CPP disease, and OA are outlined in the table (table 2) and summarized in more detail below:
●CPPD disease – CPPD can be present, with typical changes, in patients with HH. However, unique radiographic differences are seen in some patients that distinguish primary CPPD disease from the disorder associated with HH. (See 'Cartilage calcification (chondrocalcinosis)' above and "Calcium pyrophosphate crystal deposition (CPPD) disease: Clinical manifestations and diagnosis".)
●Osteoarthritis – Typical osteoarthritis (OA) of joints that have a propensity to be involved in HH arthritis (eg, index and middle finger metacarpophalangeal [MCP] joints) may be increased in prevalence among patients who are heterozygous for HFE mutations and who are not iron overloaded [8]; although there is no association with OA elsewhere [7]. A case-controlled study has demonstrated a significant association between HH and OA [68], and a significant association was also observed between HFE gene mutations and primary OA in the ankle [73]. (See "Clinical manifestations and diagnosis of osteoarthritis".)
In a study comparing features of HH arthropathy and idiopathic hand OA, involving a total of 299 patients (141 with HH arthropathy of the hands and 158 with idiopathic hand OA), patients with HH arthropathy were younger and predominantly male; in the males, HH arthropathy led to an earlier start of symptoms than in idiopathic hand OA [74]. Patients with hand OA had more tender joints and worse hand function than patients with HH arthropathy. MCP and wrist joint involvement was more frequent and severe in HH arthropathy, while hand OA patients more frequently had degenerative changes in the first carpometacarpal (CMC) as well as proximal interphalangeal (PIP) and distal interphalangeal (DIP) joints.
●Rheumatoid arthritis – The distribution of joint involvement and acute attacks of synovitis in HH may be similar to that seen in patients with RA. Patients with HH do not have the characteristic small joint changes found in RA (eg, swan neck deformity with hyperextension of the PIP joint and flexion of the DIP joint). Ulnar deviation, a common finding in RA, has not been reported in HH. Rheumatoid factor testing may occasionally be positive in HH arthropathy, but anti-citrullinated peptide antibodies are rarely present and may be helpful in distinguishing the arthropathy of HH from RA [75]. (See "Diagnosis and differential diagnosis of rheumatoid arthritis".)
TREATMENT —
The treatment of arthritis in patients with hereditary hemochromatosis (HH) is very similar to the approach to the treatment of osteoarthritis (OA) and calcium pyrophosphate crystal deposition (CPPD) disease in patients without HH.
●Analgesia and supportive care – Patients may benefit from analgesics (eg, acetaminophen) and general measures for joint protection, which are described in detail elsewhere. (See "Overview of joint protection".)
●Antiinflammatory therapy
•Initial therapy – For most patients with HH arthropathy, we suggest treatment with an antiinflammatory therapy (specifically a nonsteroidal antiinflammatory drug [NSAID] or colchicine) rather than systemic glucocorticoids. Any NSAID may be used at typical antiinflammatory doses (eg, naproxen, ibuprofen, celecoxib). The dosing, contraindications, and monitoring of NSAIDs and colchicine for arthritis from HH are the same as when these agents are used to treat CPPD disease. (See "Treatment of calcium pyrophosphate crystal deposition (CPPD) disease", section on 'Chronic CPP crystal inflammatory arthritis' and "Treatment of calcium pyrophosphate crystal deposition (CPPD) disease", section on 'Acute CPP crystal arthritis (pseudogout)'.)
An alternative option in patients with a few involved joints in whom joint injection is feasible is to administer intraarticular glucocorticoids. Procedural guidance, medication dosing, and contraindications for arthrocentesis are provided separately. (See "Joint aspiration and injection in adults: Indications and technique" and "Intraarticular and soft tissue injections: What agent(s) to inject and how frequently?".)
•Treatment of persistent disease – In order to prevent disability, it is important to monitor for ongoing synovitis, which can be appreciated clinically and on imaging (eg, ultrasound). In patients with evidence of low-grade inflammation (eg, synovitis on examination or imaging) with an inadequate response to NSAIDs or colchicine, we suggest a short course of systemic glucocorticoids (eg, prednisone) rather than other immunosuppressive therapies. Intraarticular glucocorticoids can also be added for those with involvement of joints that are amenable to injection. The dosing, contraindications, and monitoring of these therapies in arthritis related to HH are the same as when they are used to treat CPPD disease. (See "Treatment of calcium pyrophosphate crystal deposition (CPPD) disease", section on 'Glucocorticoids' and "Treatment of calcium pyrophosphate crystal deposition (CPPD) disease", section on 'Inadequate response to NSAIDs'.)
For patients who do not respond to or cannot tolerate the above therapies, additional options include agents that are used for refractory forms of chronic CPP crystal inflammatory arthritis (eg, hydroxychloroquine or, rarely, interleukin 1 [IL-1] inhibition for ongoing synovitis causing disability), as described elsewhere. (See "Treatment of calcium pyrophosphate crystal deposition (CPPD) disease", section on 'Inadequate response to NSAIDs' and "Treatment of calcium pyrophosphate crystal deposition (CPPD) disease", section on 'Resistant to initial and second-line therapies'.)
•Evidence – NSAIDs, colchicine, and glucocorticoids are effective for symptomatic relief in our experience and in the experience of others, but there is no evidence that they reduce the progression of joint damage [76-78]. There are no published systematic studies or randomized trial experience in treating the arthritis in HH. Our preference to use colchicine or NSAIDs as first-line therapy is based on our clinical experience as well as the relative adverse effect profiles of the different antiinflammatory agents.
●Management of hemochromatosis – Treatment of HH by phlebotomy generally has little effect upon the clinical, radiologic, or histologic progression of the arthropathy. In one series, for example, only 20 percent of 129 patients noted improvement in joint symptoms after phlebotomy [79]. The effects of iron chelation on the symptoms of arthritis the progression of the arthropathy are not known. Patients should be managed in collaboration with an expert in the treatment of iron overload disorders and other relevant specialists depending upon the patient's clinical manifestations. The management of patients with hereditary hemochromatosis is described in detail separately. (See "Management and prognosis of hereditary hemochromatosis".)
Specific dietary limitations advised in patients with HH are described in detail separately. (See "Management and prognosis of hereditary hemochromatosis", section on 'Addressing concerns about dietary iron'.)
●Treatment of comorbid conditions
•Osteoarthritis – Patients who require primary total hip arthroplasty for severe secondary OA may be at increased risk of aseptic loosening of the prosthetic. The treatment of OA is described in detail separately. (See "Overview of the management of osteoarthritis" and "Treatment of calcium pyrophosphate crystal deposition (CPPD) disease".)
•Osteoporosis – Bone densitometry should be carried out in all patients with HH. Management of HH-related osteoporosis is no different from osteoporosis due to other causes. (See "Evaluation and treatment of premenopausal osteoporosis" and "Overview of the management of low bone mass and osteoporosis in postmenopausal women" and "Treatment of osteoporosis in men".)
PROGNOSIS —
The arthropathy of hereditary hemochromatosis (HH) may significantly affect the quality of life. One study of 50 consecutive patients, for example, found that the manifestations of arthritis, as compared with those of diabetes and cirrhosis, was the single most prominent factor affecting the patient's perception of quality of life [80].
Patients with HH are at increased risk of needing to undergo joint replacement surgery because of severe secondary OA [4]. However, patients who require primary total hip arthroplasty (THA) and who are homozygous for the C282Y mutation of the HFE gene have an increased risk of developing aseptic loosening, leading to revision THA [81,82].
Patients with HH who develop related arthritis may be at higher risk of having advanced liver disease. In an observational study of 112 patients with HH, 47 (42 percent) had arthritis, which was associated with advanced hepatic fibrosis as measured by liver biopsy (relative risk 7.4, 95% CI 2.5-23), the aspartate aminotransferase to platelet ratio index (relative risk 4.5, 95% CI 2.0-10.2), and the fibrosis 4 index (relative risk 2.2, 95% CI 1.1-4.6) [83].
More information on the prognosis of patients with HH is provided separately. (See "Management and prognosis of hereditary hemochromatosis", section on 'Prognosis'.)
SUMMARY AND RECOMMENDATIONS
●Pathogenesis – About one-half of patients with hereditary hemochromatosis (HH), if untreated, eventually develop arthritis. Iron deposition and defects in cartilage and in immunologic function have been implicated as factors that contribute to the development of arthritis in HH. (See 'Pathogenesis' above and 'Clinical features' above.)
●Joint pathology – Synovial tissue in HH is brown because of iron deposition. Abnormal amounts of iron deposits, few or no signs of synovial inflammation, and calcium pyrophosphate crystal deposition (CPPD) are characteristic findings upon microscopic examination. Neutrophil invasion of the synovium may be seen, particularly in joints with increased iron deposition. In addition, crystals can be found in the absence of iron deposits. (See 'Joint pathology' above.)
●Clinical features
•Clinical manifestations – Arthritis may be the presenting symptom of HH, but rheumatic symptoms can occur after the diagnosis has been made. Some patients experience only mild arthralgia. The metacarpophalangeal (MCP) joints, especially the second and third MCP, and the wrists are commonly affected. Bilateral destruction of the MCP joints and reduced flexion may occur. Other involved joints frequently include the hips, knees, and shoulders and sometimes cause severe disability requiring surgery. Acute arthritis flares related to CPPD may occur; however, cartilage calcification (chondrocalcinosis) is common and usually asymptomatic in patients with HH. (See 'Clinical features' above.)
•Imaging – Arthritis among patients with HH is characterized radiographically by several patterns, including isolated cartilage calcification (chondrocalcinosis); hypertrophic osteoarthritis (OA), which is indistinguishable radiologically from CPPD-associated arthropathy; and disease-specific changes which include subchondral radiolucency of the femoral head, hook-like osteophytes on the metacarpal heads, and a degenerative predilection for the MCP joint rather than the scapholunate. Cartilage calcification most frequently involves the knees and wrists, while the hips, symphysis pubis, and spine may also be affected. (See 'Imaging' above and 'Cartilage calcification (chondrocalcinosis)' above.)
•Associated osteoporosis – A significant decrease in bone density is frequently observed among patients with HH and other forms of iron overload, particularly those with concurrent hypogonadism, but osteoporosis can also be seen in eugonadal subjects. Bone densitometry should be performed in patients with HH, and reduced bone mass is managed as in other patients without HH. (See 'Osteoporosis and osteoarthritis' above.)
●Diagnosis – The diagnosis is made in a patient with one of the characteristic forms of arthritis in the presence of HH. HH is suggested by increases in transferrin saturation and the serum ferritin concentration; it is confirmed by genetic testing. (See 'Diagnosis' above and "Approach to the patient with suspected iron overload".)
●Differential diagnosis – In general, the differential diagnosis includes any cause of an inflammatory arthropathy, but the principal joint disorders which must be distinguished from the arthropathy of HH are primary CPPD disease and rheumatoid arthritis (RA). (See 'Differential diagnosis' above.)
●Treatment – The management HH arthropathy includes analgesia, supportive care, antiinflammatory therapy, and treatment of hemochromatosis and other comorbid conditions (eg, OA); it is very similar to the management approach used for patients with OA and CPPD disease who do not have HH.
•Initial treatment – For most patients with HH arthropathy, we suggest treatment with a nonsteroidal antiinflammatory drug (NSAID) or colchicine, rather than systemic glucocorticoids (Grade 2C). Any NSAID may be used at typical antiinflammatory doses. An alternative option in patients with a few involved joints in whom joint injection is feasible is to administer intraarticular glucocorticoids. (See 'Treatment' above.)
•Treatment of persistent disease – In patients with evidence of ongoing low-grade inflammation (eg, synovitis on examination or imaging) despite a trial of an NSAID or colchicine, we suggest a short course of systemic glucocorticoids (eg, prednisone) rather than other immunosuppressive therapies (Grade 2C). Intraarticular glucocorticoids can also be added. (See 'Treatment' above.)
●Prognosis – Patients who require primary total hip arthroplasty may be at increased risk of aseptic loosening of the prosthetic. (See 'Prognosis' above.)
