Is there a connection between hemochromatosis and arthritis?

Hemochromatosis and Arthritis: A Definitive Connection

Yes, there is a strong and well-established connection between hemochromatosis and arthritis—arthropathy occurs in approximately 72-87% of patients with hemochromatosis and represents one of the most common and debilitating manifestations of the disease. 1, 2

Epidemiology and Clinical Significance

The relationship between hemochromatosis and joint disease is substantial and impacts quality of life significantly:

• Non-infectious arthropathies occur 2.38 times more frequently in patients with hemochromatosis compared to those without the condition (HR 2.38,95% CI 2.14-2.64). 1

• Joint pain is reported by 72.4% of hemochromatosis patients, making it one of the most common symptoms—even more prevalent than fatigue in some cohorts. 2

• In patient surveys, 86.5% described arthritis or joint pain, with musculoskeletal symptoms affecting ankles (69.3%), hips (56.8%), and hands/wrists (46.9%). 1

• Joint symptoms typically precede the diagnosis of hemochromatosis by an average of 9 years, with initial symptoms appearing around age 45.8 years. 2

Characteristic Pattern of Hemochromatosis Arthropathy

The arthropathy has a distinctive clinical and radiographic presentation that differentiates it from typical osteoarthritis:

Joint Distribution

• Classic involvement of the 2nd and 3rd metacarpophalangeal (MCP) joints is pathognomonic, occurring in nearly all patients with hemochromatosis arthropathy. 1, 3

• Large joints are frequently affected, particularly ankles, hips, and knees—not just the hands. 1, 2

• The pattern can mimic rheumatoid arthritis, particularly when MCP joints are involved, leading to potential misdiagnosis. 4

Clinical Features

• Younger age of onset compared to typical osteoarthritis. 1

• Bony enlargement occurs in 65.8% of patients, while synovitis is less common (13.6%). 2

• Rapid progression to cartilage loss with exuberant osteophyte formation. 1

Radiographic Findings

• Joint space narrowing, osteophytes, and subchondral cysts are characteristic. 1

• Chondrocalcinosis is present in 50% of cases, representing calcium pyrophosphate deposition disease (CPPD). 1, 5

• Iron deposition in joints is not universally observed, suggesting the pathogenesis involves more than direct iron toxicity. 1

Pathophysiology: Why Iron Causes Arthritis

The mechanism linking iron overload to joint disease involves multiple pathways:

• Increased neutrophil invasion in the synovium is markedly elevated in hemochromatosis arthropathy, especially in joints with iron deposition, which accelerates cartilage degradation. 1

• Direct chondrocyte and bone cell damage from excess iron occurs in vitro, though animal models show inconsistent direct cartilage effects. 5

• Decreased osteoblast alkaline phosphatase activity and increased osteoclastogenesis lead to abnormal bone metabolism and generalized bone loss. 5

• Impaired joint repair mechanisms may be shared between hemochromatosis arthropathy and CPPD, relating more to bone abnormalities than direct cartilage damage. 5

• Iron load is a major determinant: arthropathy is strongly associated with ferritin concentrations >1,000 μg/L at diagnosis (OR 14.0,95% CI 1.30-150.89). 6

Increased Risk of Joint Replacement Surgery

The severity of hemochromatosis arthropathy frequently necessitates surgical intervention:

• Hip replacement risk is increased 2.77-fold (HR 2.77,95% CI 2.27-3.38). 1

• Knee replacement risk is increased 2.14-fold (HR 2.14,95% CI 1.58-2.88). 1

• Single total hip replacement risk is increased 1.94-fold (HR 1.94,95% CI 1.04-3.62), while bilateral total hip replacement risk is increased 5.86-fold (OR 5.86,95% CI 2.36-14.57). 1

• 16.1% of hemochromatosis patients undergo total joint replacement surgery at a mean age of 58.3 years—significantly younger than typical osteoarthritis patients. 2

• Female sex, MCP joint involvement, and presence of chondrocalcinosis are associated with higher risk of early joint failure requiring replacement. 2

Critical Treatment Limitation: Phlebotomy Does Not Help Arthritis

This is the most important clinical pitfall to understand:

• Hemochromatosis arthropathy does not respond to phlebotomy and can even develop or progress during maintenance therapy. 1

• Phlebotomy may alleviate early constitutional symptoms but does not help established arthritis. 3

• Treatment is limited to symptomatic management: analgesics, NSAIDs, physiotherapy, and ultimately joint replacement surgery. 1

• Some evidence suggests iron chelating drugs may be necessary in addition to phlebotomy for articular manifestations, though this is not standard practice. 4

• Symptoms significantly affect quality of life despite adequate iron depletion therapy. 1

Clinical Implications for Practice

When to Screen for Hemochromatosis in Arthritis Patients

Consider hemochromatosis screening when patients present with:

• Arthritis involving 2nd and 3rd MCP joints, especially with ankle involvement. 1, 7

• Early-onset atypical arthropathy (before age 50) with rapid progression. 7

• Chondrocalcinosis on radiographs, particularly in younger patients. 1

• Arthritis that fails to respond to standard disease-modifying drugs, as these medications are hepatotoxic and worsen outcomes in undiagnosed hemochromatosis. 4

Diagnostic Approach

• Initial screening with transferrin saturation (≥45%) and serum ferritin (>200 μg/L in females, >300 μg/L in males). 1, 7, 8

• HFE genetic testing for C282Y homozygosity if iron studies are elevated. 1, 7

• All patients with hemochromatosis should be clinically evaluated for joint disease as part of their initial assessment. 1, 9

Management Strategy

• Initiate phlebotomy immediately to prevent progression of other organ damage (liver, heart, pancreas), even though it will not reverse established arthritis. 7, 9

• Manage arthritis symptomatically with NSAIDs, intra-articular corticosteroid injections, and physical therapy. 3

• Avoid disease-modifying antirheumatic drugs (DMARDs) if hemochromatosis is present, as they are hepatotoxic and the liver is the major site of iron deposition. 4

• Early referral to orthopedic surgery should be considered given the high rate of joint replacement and younger age at which it occurs. 2

• Maintain ferritin between 50-100 μg/L during maintenance phase to prevent further iron accumulation, though this will not improve existing arthropathy. 9