Hemochromatosis

Introduction

The most common form of hereditary hemochromatosis (HH) is an autosomal recessive iron-overload disorder associated with mutation of the HFE gene, located on chromosome 6. Approximately 90% of subjects with HH who are of northern European descent are homozygous for a missense mutation that results in the substitution of a tyrosine for cysteine at position 282 of the HFE protein (C282Y). This mutation impairs HFE protein signaling and leads to reduced expression of hepcidin mRNA and decreased plasma hepcidin levels, resulting in increased iron release from splenic macrophages and enterocytes into plasma.

Another mutation in the HFE gene can result in the substitution of aspartate for histidine at amino acid 63 (H63D). About 5% of people with HH may show compound heterozygosity for both the C282Y and H63D mutation. The phenotype of affected individuals is generally less severe.

The prevalence of the HFE homozygosity varies among ethnic groups. In Europe and North America, the average prevalence for C282Y homozygosity and C282Y heterozygosity is 0.4% to 0.5% and 9%, respectively. In Asian, Indian subcontinent, African, Middle Eastern, and indigenous Australasian populations, C282Y homozygosity is very rare, although the frequency of C282Y heterozygosity ranged from 0% to 0.5%.

Increased plasma iron levels lead to increased iron transport into parenchymal cells, notably hepatocytes, pancreatic cells, and cardiomyocytes, leading to predominantly hepatic, pancreatic, and cardiac iron overload, with subsequent damage to structure due to reactive oxygen species induced by iron excess. Once transferrin saturation exceeds 50%, nontransferrin-bound iron, a toxic form of iron, occurs and might be responsible for most tissue damage.

Studies of human joint tissue have shown hemosiderin accumulation in the cartilage and synovial tissue, and increased ferritin levels in the synovial fluid of affected joints has been reported. Similarly, a mouse model of HH found abnormal iron deposits at the bone trabecular surface.

The penetrance of C282Y homozygosity is incomplete, and there is a large variability of the phenotype: biochemical expression (increase in the transferrin saturation >45%, the earliest biochemical sign observed in HH, followed by increase in the ferritin levels) precedes clinical expression. Overall, first symptoms will develop at 30 to 40 years of age in men and 40 to 50 years of age in women. Environmental factors and associated modifying genes modulate phenotypic expression.

The classic well-known clinical manifestations of HH, hepatic cirrhosis, diabetes, skin pigmentation, and cardiac involvement, are becoming very rare and are usually seen in individuals with a serum ferritin concentration largely exceeding 1000 μg/L. Nowadays, the most common symptoms of HH are chronic fatigue and joint pain.

Three main rheumatologic complications have been reported in phenotypically expressed HH: an arthropathy that mimics osteoarthritis (OA) but with a different joint distribution, chondrocalcinosis, and osteoporosis. Of note, before structural damage occurs, patients can complain with arthralgia for a long period time, notably at the hands with the classic “painful handshake.”

The Hemochromatosis Arthropathy

An arthropathy that mimics osteoarthritis (OA) has been reported to range from 20% to 80%. The association observed between this arthropathy and total-body iron burden, as determined by ferritin levels at diagnosis, suggests that iron load is a major determinant of arthropathy in HH. This arthropathy appears quite rare when ferritin levels are below 1000 μg/L at diagnosis. The mean delay between the first joint pain and the diagnosis of HH is close to 8 years.

The arthropathy of HH is chronic and progressive. Although all joints can virtually be involved, it most often affects the MCPs 2 and 3, the wrists, the ankles, and the knees. The involvement of the MCP 2, 3 joints, when severe, can be appreciated on clinical examination. Lack of flexion in these joints accounts for the “iron fist” sign ( Fig. 212.1 ). This particular joint distribution at the hand is very evocative of the disease and different from idiopathic hand OA. Importantly, MCPs 2,3 involvement is a marker of disease severity as it is a predictor of large joint replacement.

Ultrasound studies found a high frequency of synovitis at the hand, correlated with structural damage. Although the hand arthropathy presents in the majority of cases as a noninflammatory condition, it can mimic rheumatoid arthritis, due to the bilateral MCPs 2,3 involvement often associated with synovitis ( Fig. 212.2 ). Apart from the hips and the knees, ankle involvement that resembles OA is another feature very evocative of HH in the absence of prior traumatism.

These arthropathies can be severe, with a huge impact on patients’ quality of life, often leading to joint replacement at the hips, knees, and ankles, despite iron removal.

Of note, HH-related arthropathy is more severe in patients with C282Y homozygosity than C282Y–H63D compound heterozygotes, a finding that might be related to the more severe iron overload in C282Y homozygotes.

Chondrocalcinosis

Chondrocalcinosis, i.e., calcium deposits within cartilage and fibrocartilage, is a common finding in patients with HH. In the largest case series, the prevalence of chondrocalcinosis ranged from 20% to 30% in patients with HH-related arthropathy. Chondrocalcinosis is occasionally found even in the absence of clinical or radiologic evidence of arthropathy. Despite the relative high frequency of calcium deposits, acute calcium pyrophosphate (CPP) arthritis, formerly known as pseudogout, is rather uncommon. Chondrocalcinosis is as well a risk factor for joint replacement surgery.