Haemochromatosis Arthropathy

What it is. Haemochromatosis arthropathy is the joint disease of hereditary (primary) haemochromatosis, an inherited disorder of iron metabolism in which excessive intestinal iron absorption leads to progressive tissue iron overload. Iron accumulates in the liver, pancreas, heart, pituitary and skin, and also in synovium and cartilage, where it produces a distinctive degenerative arthropathy.

Why it matters to the orthopaedic surgeon. The arthropathy is frequently the presenting feature, it mimics osteoarthritis in joints that primary OA usually spares, and it is largely irreversible even once the iron overload is treated. Joint pain is reported by around 70-75% of patients with iron overload; in one large cohort it was present in 72% and preceded the diagnosis of haemochromatosis by an average of about 9 years. The orthopaedic surgeon or rheumatologist who recognises MCP osteoarthritis or chondrocalcinosis and orders iron studies is therefore well placed to make the diagnosis early.

Genetics. Most cases are due to homozygosity for the C282Y mutation in the HFE gene on chromosome 6; compound heterozygosity (C282Y/H63D) is a less penetrant cause. Inheritance is autosomal recessive, and clinical penetrance is incomplete and modified by sex, blood loss and alcohol.

Epidemiology. Haemochromatosis is one of the commonest inherited disorders in people of Northern European ancestry, in whom C282Y homozygosity occurs in roughly 1 in 200 to 1 in 400. It is much rarer in South American, African and East Asian populations, where the C282Y mutation is uncommon and the diagnostic algorithm differs. Men present earlier and more severely than women, who are partially protected by menstrual and pregnancy blood loss.

The disease discussed here is hereditary (primary) haemochromatosis, but iron-overload arthropathy can also arise from secondary (acquired) iron loading, and the distinction changes the genetics, the systemic context and, importantly, the treatment.

The treatment column is the point. Primary iron overload is venesected, whereas the transfused patient is anaemic, so venesection is impossible and iron chelation is used instead. Juvenile haemochromatosis presents young with severe cardiac and endocrine disease. All forms can produce an iron arthropathy and chondrocalcinosis.

Systemic iron loading. HFE dysfunction reduces hepcidin, the master iron-regulatory hormone, so enterocytes and macrophages export iron unchecked through ferroportin and intestinal absorption goes unrestrained. Transferrin becomes saturated and non-transferrin-bound iron circulates, depositing in parenchymal tissues including synovium and cartilage. Histologically the iron is visible as haemosiderin in synovial lining cells and chondrocytes.

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What drives the joint damage. The arthropathy results from chronic iron deposition in joint tissues. Unlike gout or CPPD, the dominant mechanism appears to be iron-driven damage to bone and cartilage cells rather than a single crystal trigger, although crystal disease frequently coexists.

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Direct cellular toxicity. Excess intracellular iron catalyses reactive oxygen species through Fenton chemistry, causing oxidative stress. In chondrocytes, iron exposure increases catabolic enzymes (the matrix metalloproteinases MMP3 and MMP13), reduces extracellular matrix and aggrecan production, and pushes the cells toward a hypertrophic, osteoarthritis-like phenotype. Iron-loaded synovium becomes inflamed and contributes to cartilage breakdown.

Bone-centred mechanisms, shared with CPPD. Iron overload reduces osteoblast alkaline phosphatase activity and increases osteoclastogenesis, producing generalised bone loss and impaired joint repair. These abnormalities of bone turnover and of damage and repair are strikingly similar to those seen in CPPD, which may explain why the two diseases overlap and why haemochromatosis arthropathy can occur even without demonstrable CPP crystals.

The link with calcium pyrophosphate deposition. Haemochromatosis is one of the classic metabolic associations of CPPD. Iron may inhibit pyrophosphatases or otherwise favour calcium pyrophosphate crystal formation, and the shared effects on bone cells link the two. Chondrocalcinosis is a common radiographic finding, and acute pseudogout attacks can occur.

Why venesection does not cure the joint. By the time the arthropathy is clinically apparent, iron has already triggered chondrocyte catabolism, matrix loss and disordered bone remodelling. Removing circulating iron by venesection halts ongoing systemic damage but cannot reverse established cartilage and bone destruction, so the arthropathy characteristically progresses despite adequate iron-depletion therapy.

Because haemochromatosis is one of the metabolic causes of calcium pyrophosphate deposition, finding chondrocalcinosis - especially in a younger patient (under about 55), when it is florid or polyarticular, or in atypical joints - should prompt a screen for the secondary metabolic causes, not just haemochromatosis.

Ageing and osteoarthritis are by far the commonest setting for CPPD overall, and familial forms (ANKH gene mutations) exist; but it is the metabolic causes above, haemochromatosis being the surgically important one, that must not be missed in a young or atypical presentation.

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Small-joint disease, the classic pattern. Insidious pain, stiffness and bony swelling of the 2nd and 3rd metacarpophalangeal joints, often bilateral and symmetrical, with reduced grip and difficulty making a fist. The wrists are also commonly involved. The pattern resembles osteoarthritis, but in joints that primary OA usually spares.

Large-joint disease. The hips, knees, ankles and shoulders may develop a destructive OA-like arthropathy. Ankle involvement is increasingly recognised and can be a major source of disability. Large-joint disease is a frequent reason for joint replacement, sometimes at a relatively young age.

Acute presentations. Coexisting chondrocalcinosis can produce acute pseudogout (acute CPP crystal arthritis): a hot, swollen joint, often the knee or wrist. An acute monoarthritis must always be distinguished from septic arthritis.

The systemic context. The associated features of iron overload are the diagnostic context for the joint complaint:

• Liver: hepatomegaly, deranged liver function, cirrhosis, hepatocellular carcinoma
• Pancreas: diabetes mellitus ("bronze diabetes") from pancreatic iron deposition
• Skin: bronze or slate-grey pigmentation, melanin plus iron deposition
• Heart: cardiomyopathy, heart failure, arrhythmia
• Endocrine and gonadal: pituitary and gonadal iron causing hypogonadism, impotence and low testosterone; fatigue
• Haematology: a high-normal or raised mean corpuscular volume (MCV) is associated with the presence of arthritis in haemochromatosis

Examination. Look for bony enlargement of the 2nd and 3rd MCP joints, the squared knuckles, and for effusions in the larger joints during acute crystal attacks. The swelling is hard and bony rather than boggy; synovitis is the minority. Range and grip are reduced, with crepitus in established large-joint OA. Look too for skin pigmentation and the stigmata of chronic liver disease.

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Iron studies. Transferrin saturation is the most useful initial screening test; a fasting value above approximately 45% in women or 50% in men is suggestive. Serum ferritin reflects iron stores but is an acute-phase reactant, so it is interpreted together with the transferrin saturation. Order both in anyone with MCP osteoarthritis, unexplained chondrocalcinosis or premature large-joint OA.

Confirmation. HFE genotyping showing C282Y homozygosity (or compound C282Y/H63D heterozygosity) confirms hereditary haemochromatosis in a patient with biochemical iron overload. In populations where C282Y is rare, or with non-HFE genotypes, MRI quantification of hepatic iron or liver biopsy is used to demonstrate the iron overload. End-organ damage is then assessed with liver function tests, fasting glucose or HbA1c, and fibrosis staging.

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Synovial fluid. An acute hot joint is aspirated and the fluid sent for crystals and culture, to identify coexisting CPP crystals (rhomboid, positively birefringent) and to exclude sepsis. Crystals never exclude infection; treat as septic if in doubt.

Plain radiographs are the key examination. The signature is squared metacarpal heads with hook-shaped osteophytes on the radial aspect of the 2nd and 3rd metacarpal heads, which is near-pathognomonic, together with subchondral cysts and uniform joint space narrowing. Chondrocalcinosis is seen in the wrists, knees, symphysis pubis and other fibrocartilage, and the large joints show OA-like changes, sometimes severe and sometimes at an unusually young age.

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MRI. T2*-weighted (gradient-echo) sequences show low-signal "blooming" from iron and haemosiderin in the synovium, and MRI demonstrates the associated cartilage loss and the meniscal and ligamentous changes.

Differential diagnosis. The exam test is to recognise that "osteoarthritis" of the MCP joints is not ordinary OA.

Treating the iron overload. Venesection (phlebotomy) is the first-line treatment for hereditary haemochromatosis: induction phlebotomy until iron stores are depleted (target ferritin low, for example below approximately 50 micrograms/L during induction), then maintenance. It prevents and can reverse liver, cardiac and endocrine damage and improves survival when started before cirrhosis. Where venesection is contraindicated or impractical, mainly when anaemia precludes it, iron-chelation therapy (for example deferasirox) is an alternative, and erythrocytapheresis is used in some centres.

Managing the arthropathy. Analgesia and judicious NSAIDs, mindful of liver disease and renal function; hand therapy, joint protection and activity modification for MCP disease; physiotherapy and weight management for large-joint OA. Acute pseudogout attacks are managed with NSAIDs, colchicine, or intra-articular or oral corticosteroids after excluding sepsis. There is no disease-modifying drug that dissolves joint iron or reverses the arthropathy. Treat metabolic comorbidities and screen first-degree relatives.

Algorithm

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Indications. Surgery is considered for:

1. End-stage large-joint OA (hip, knee, ankle, shoulder) with pain and functional loss refractory to conservative care
2. Disabling MCP/hand disease - selected cases may benefit from hand surgery, though small-joint reconstruction is less commonly required
3. Mechanical derangement - e.g. meniscal pathology or loose bodies

Arthroplasty. Iron overload is not a contraindication to arthroplasty and outcomes are generally good. Joint replacement is common in this population: in cohort data around 16% of patients underwent total joint replacement for severe OA, at a mean age in the late 50s. Female sex, MCP joint involvement and chondrocalcinosis predict earlier joint failure and the need for replacement.

Before elective surgery. Optimise iron control and assess hepatic, cardiac and endocrine status; screen for and plan around diabetes and cardiomyopathy; and exclude active crystal arthritis or infection before implanting a prosthesis.

The ankle. Conservative measures are tried first. Surgery, whether ankle arthrodesis or total ankle arthroplasty, is considered the definitive option for end-stage ankle disease.

Other procedures. Arthroscopic management of mechanical symptoms (loose bodies, meniscal tears), and synovectomy, occasionally performed for iron-laden inflamed synovium, though the evidence is limited.

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Of the disease.

• Progressive joint destruction despite iron-depletion therapy
• Acute pseudogout flares from coexisting CPPD
• Generalised bone loss and osteoporosis, related to the effects of iron on bone cells and to hypogonadism
• Systemic morbidity - cirrhosis, hepatocellular carcinoma, diabetes, cardiomyopathy, hypogonadism - all relevant to perioperative risk

Of surgery.

• Increased anaesthetic and bleeding risk in patients with significant liver disease
• Impaired glycaemic control and infection risk in those with diabetes
• The standard risks of arthroplasty; a crystal flare can occur perioperatively
• Continued symptoms in other joints as the systemic arthropathy progresses

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Haemochromatosis arthropathy is a global disease wherever iron overload occurs, but the genetic background and diagnostic algorithm differ by population. International guidance agrees on two principles: detect and treat iron overload early to protect the liver and heart, and manage the joints on their own merits because the arthropathy is largely irreversible.

Global epidemiology

• HFE C282Y homozygosity is common in people of Northern European ancestry (roughly 1 in 200 to 1 in 400) and is the dominant cause there.
• In South American, African and East Asian populations the C282Y mutation is rare, so diagnosis relies more on biochemical iron overload plus MRI-quantified hepatic iron or biopsy and consideration of non-HFE genotypes.
• Joint pain affects around 70-75% of patients with iron overload and frequently precedes diagnosis by years.

Side-by-side guidance

Registry and arthroplasty evidence

• Large arthroplasty registries (NJR, AOANJRR, AJRR, Swedish/Norwegian) do not list haemochromatosis as a distinct indication, but cohort data show joint replacement is common (about 16% of patients) with generally good results, driven by severe large-joint OA.
• Implication: standard implant and bearing selection applies; haemochromatosis changes perioperative medical optimisation, not prosthesis choice.

High- vs limited-resource practice variation

• Well-resourced settings: HFE genotyping, MRI iron quantification and structured venesection programmes are readily available; T2*-weighted MRI can demonstrate joint iron.
• Limited-resource settings: diagnosis often rests on transferrin saturation, ferritin and plain radiographs (the hook-osteophyte pattern); venesection remains low-cost and effective, while chelation is reserved for those who cannot be venesected.
• Everywhere: recognise the MCP/chondrocalcinosis pattern, screen for iron overload, treat systemic disease early, and screen first-degree relatives.

Haemochromatosis arthropathy remains incompletely understood, which makes it good higher-order viva material.

The exact mechanism of joint damage. Whether iron acts mainly through direct chondrocyte toxicity, through disordered bone remodelling, or via promotion of CPP crystals is still debated, and animal models do not always reproduce direct cartilage damage.

The relationship with CPPD. The two diseases overlap clinically and share bone-centred pathways, but it is unclear how much of the arthropathy is "iron arthropathy" and how much is secondary CPPD.

No joint-specific therapy. Nothing reliably removes iron from cartilage or reverses the arthropathy, and iron chelation has not been shown to treat the established joint disease.

Whom and when to screen. The yield of iron studies in isolated hand OA, set against the value of early detection in protecting the liver and heart, influences screening thresholds, which vary between guidelines.

The timing of large-joint surgery. In patients who may also have liver disease and diabetes the timing is individualised, with limited high-level evidence.