Hemochromatosis Arthropathy Research Articles

E064 A rare hereditary haemochromatosis type three (3) related arthritis

Abstract Background/Aims Arthritis is a common manifestation in hereditary haemochromatosis (HHC). Haemochromatosis arthropathy frequently involves small joint of hands especially the metacarpo-phalangeal joints (MCPJs) and hence is one of the differentials when assessing for rheumatoid arthritis, psoriatic arthritis along with osteoarthritis but requires a high index of suspicion. We report a case of Haemochromatosis arthropathy where the arthropathy was due to type 3 hereditary haemochromatosis (HHC) which is a much rarer form and requires specialist genetic testing. Methods A 38-year-old lady was referred with abnormal iron profile and ten-month history of small joint arthralgia mainly affecting the index and middle finger in right hand with occasional swelling. She had a normal body mass index with minimal alcohol intake. Clinical examination showed low grade synovitis in index finger metacarpo-phalangeal joint (MCPJ). Blood investigations for Rheumatoid arthritis and connective tissue diseases were negative with normal CRP & ESR, Ferritin was slightly raised at 236 and transferrin saturation was 100% on two successive occasions, LFTs were normal. Xray of hands showed slight narrowing of 2nd MCPJ and US hands showed thickened synovium but no erosions or Doppler activity in 2nd MCPJ. Results Based on these, possible hereditary haemochromatosis (HHC) arthropathy was considered. By that time, she had been seen by the hepatology service where no evidence of iron deposition in other organs was found. Surprisingly her genetic testing for hereditary haemochromatosis (HHC) (Cys282Y/H63D in HFE gene) was negative resulting in most common HFE-related HHC excluded. Iron studies were repeated which were still raised, hence after discussion with hepatologist and biochemist the plan was made to investigate for rarer form of hereditary haemochromatosis (HHC), genetic tests showed that she had TFR2 variant mutation which would be consistent with type 3 hereditary haemochromatosis (HHC), which is inherited in autosomal recessive pattern. Venesections were started with ferritin levels improving to less than 50 with plans to monitor arthralgia to see if there is any improvement over time. Conclusion Metacarpo-phalangeal joints (MCPJs) involvement is common in various arthropathies. This case highlights the importance of considering other, much rarer forms of hereditary haemochromatosis (HHC) as treatment will help in preventing iron deposition in other organs like liver, heart, pancreas etc. These conditions are very rare and there is need to create awareness of genetic testing as hereditary haemochromatosis (HHC) arthropathy does present not uncommonly to rheumatology services and requires dedicated non-HFE molecular panel. Disclosure H. Umair: None. M. Kazmi: None.

HLA-A*03, the hemochromatosis ancestral haplotype, and phenotypes of referred hemochromatosis probands with HFE p.C282Y homozygosity

BackgroundHuman leukocyte antigen (HLA)-A*03, hemochromatosis ancestral haplotype marker, was associated with greater iron overload in hemochromatosis cohorts reported before discovery of the HFE gene. We sought to learn whether an A*03-linked locus influences phenotypes in referred HFE p.C282Y homozygotes.MethodsWe tabulated these phenotypes in probands with p.C282Y homozygosity: age, transferrin saturation (TS), serum ferritin (SF), conditions related to iron overload, fibrosis-four variables (FIB-4) index and aspartate aminotransferase-to-platelet ratio index (APRI) predictors of severe hepatic fibrosis, and iron removed to achieve depletion (QFe/age). We analyzed phenotypes of men and women separately across three A*03 subgroups.ResultsThere were 104 men (57.8%) and 76 women (42.2%). Mean age (SD) was 49 ± 13 y. Mean TS was 79 ± 17%. Median SF (range) was 715 µg/L (28, 6103). Related conditions included: hemochromatosis arthropathy (21.7%); type 2 diabetes (18.9%); hypogonadotropic hypogonadism (5.8% of men); cardiomyopathy (0%); and cirrhosis (10.0%). Median QFe/age was 61 mg/y (0, 714). A*03 homozygosity, heterozygosity, and no A*03 occurred in 37 (20.6%), 104 (57.8%), and 39 probands (21.7%), respectively. In men, mean TS and median SF were significantly higher in A*03 homozygotes than heterozygotes but not A*03-negative probands. In men, median APRI was significantly lower in A*03 heterozygotes than homozygotes and A*03-negative probands. No other phenotypes, including QFe/age, differed significantly across A*03 subgroups in either men or women.ConclusionsOur results suggest that an A*03-linked locus does not influence phenotypes in referred HFE p.C282Y homozygotes. It is unlikely that heritable factors that modify phenotypes of p.C282Y homozygotes are linked to the hemochromatosis ancestral haplotype.

Identification of Common Pathogenic Pathways Involved in Hemochromatosis Arthritis and Calcium Pyrophosphate Deposition Disease: a Review.

Arthritis is a common clinical manifestation of hereditary hemochromatosis (HH), and HH is one of a handful of conditions linked to calcium pyrophosphate deposition (CPPD) in joints. The connection between these two types of arthritis has not yet been fully elucidated. In light of new pathogenic pathways recently implicated in CPPD involving bone, we reviewed the literature on the etiology of hemochromatosis arthropathy (HHA) seeking shared pathogenic mechanisms. Clinical observations reinforce striking similarities between HHA and CPPD even in the absence of CPP crystals. They share a similar joint distribution, low grade synovial inflammation, and generalized bone loss. Excess iron damages chondrocytes and bone cells in vitro. While direct effects of iron on cartilage are not consistently seen in animal models of HH, there is decreased osteoblast alkaline phosphatase activity, and increased osteoclastogenesis. These abnormalities are also seen in CPPD. Joint repair processes may also be impaired in both CPPD and HHA. Possible shared pathogenic pathways relate more to bone and abnormal damage/repair mechanisms than direct damage to articular cartilage. While additional work is necessary to fully understand the pathogenesis of arthritis in HH and to firmly establish causal links with CPPD, this review provides some plausible hypotheses explaining the overlap of these two forms of arthritis.

Iron triggers the early stages of cartilage degeneration in vitro: The role of articular chondrocytes

ObjectiveArthropathy is a major clinical problem in patients with hemochromatosis, the most common genetic disorder of iron overload. The pathological features of hemochromatosis arthropathy (HA) are heterogeneous and its specific nature remains unknown. One important drawback is the lack of proper in vitro models. The aim of the present study was to set up a model to investigate the biological response of cartilage to iron exposure. DesignBovine articular cartilage explants were incubated with ferric citrate for up to 9 days. We evaluated chondrocyte viability, iron deposition, and biomarkers of cartilage degradation in the conditioned medium. ResultsIron accumulated within chondrocytes, which was associated with programmed cell death through chondroptosis. Iron treatment increased the release of sulfated glycosaminoglycans (sGAG), a component of the extracellular matrix, into the medium (p=0.0189). This was dependent on the presence of viable chondrocytes and was associated with increased activity of matrix-degrading metalloproteinases (MMP) (pro/active MMP-9, p=0.0317; pro MMP-2, p=0.0092; active MMP-2, p=0.0288). Co-treatment with the broad MMP/aggrecanase inhibitor prinomastat reduced iron-mediated sGAG release (0.02 ​μM, p=0.0425; 2 ​μM, p=0.0014), confirming that iron induces sGAG release via the activation of catabolic enzymes. Notably, iron-treated cartilage continued to release an increased amount of sGAG into the medium for 6 days after termination of the ferric citrate treatment (p=0.0259). ConclusionsIron triggers the early stages of cartilage degeneration. Removal of iron exposure does not prevent further damage to the cartilage, thus providing a possible explanation why HA is not prevented after iron depletion by phlebotomy treatment.

Hemochromatosis Arthropathy in Heterozygous HFE H63D Mutation Without Iron Overload- An Entity Less Commonly Touched

Human homeostatic iron regulator protein gene (HFE gene) H63D mutations even when homozygous are rarely associated with iron overload. These mutations, independent of iron status, are associated with calcium pyrophosphate dihydrate crystal deposition disease (CPPD) leading to arthropathy even for heterozygotes. The arthropathy does not respond to iron depletion. We report a case of a 62-year-old male with chronic generalized arthralgias with no evidence of iron overload or elevated inflammatory markers with characteristic radiographic hook-like osteophytes suggestive of hemochromatosis arthropathy. Further, he was found to be a carrier of HFE H63D mutation. Recognition of the association can help guide goal directed management.

Haemochromatosis arthropathy - a conundrum of the Celtic curse.

Genetic haemochromatosis is an autosomal recessive disorder, mostly due to HFE gene mutation, leading to loss of hepcidin and unregulated iron loading. The consequences include hepatic fibrosis, cardiomyopathy and skin pigmentation, and these sequelae along with fatigue may be prevented by 'de-ironing'. Joint pain is frequently reported at diagnosis and an arthropathy that is essentially accelerated osteoarthritis may develop, with onset at a younger than expected age, involvement of typical and atypical joints, such as metacarpophalangeal and ankle, exuberant osteophytes and rapid progression to cartilage loss and the need for arthroplasty. The arthropathy differs from the other features in not responding to de-ironing, new joints becoming affected once patients are in maintenance, and, intriguingly, classic cases occur in the absence of iron overload with major and minor HFE mutations. These anomalies present a conundrum that raise the question whether HFE mutations have an arthritogenic consequence independent of hepcidin and iron.

Haemochromatosis and Arthropathies

Arthropathy is the most common and often the earliest clinical manifestation of hereditary hemochromatosis (HH). It is difficult to treat and there is a high risk for early endoprosthetic joint replacement. Research done during the last decade shows that it is a joint disease in its own right. Clinically, there are degenerative articular changes with an atypical pattern of distribution, a crystal arthropathy (CPPD) with congenital joint swelling and synovitis like in RA. The X-ray image shows typical but not exclusive findings. In MRI, groundbreaking subchondral findings are found, especially in the large joints, and ultrasound shows inflammatory lesions in non-arthropathy patients as well. In animal experiments and pathomorphological studies of the synovial membrane, the arthropathy can be differentiated from osteoarthrits and RA. The pathophysiological significance of iron overload can be distinguished from immunohistochemical and cytogenetic investigations in chronic degenerative HH arthropathy and inflammatory-destructive arthropathy in hemophilia. By elucidating the pathophysiology, new therapeutic approaches can be formulated. In addition to colchicine, the IL-1 receptor antagonist anakinra is available for activation of the NLRP3 inflammasome by CPPD crystals and subsequent induction of IL-1β overproduction. Other manifestations include symptomatic pain therapy and intensive physiotherapy and occupational therapy. To promote further research into hemochromatosis arthropathy, the Hemochromatosis Arthropathy Research Initiative (HARI) was established in 2016.

Comment on: Hereditary haemochromatosis arthropathy and Doppler ultrasound findings of synovitis: reply.

Comment on: Hereditary haemochromatosis arthropathy and Doppler ultrasound findings of synovitis: reply.

Comment on: Hereditary hemochromatosis arthropathy and Doppler ultrasound findings of synovitis.

Comment on: Hereditary hemochromatosis arthropathy and Doppler ultrasound findings of synovitis.

Hemochromatosis

Hereditary hemochromatosis is a frequent autosomal recessive iron storage disease in northern and western Europe. The classical clinical triad of liver cirrhosis, hyperpigmentation and diabetes is nowadays rare, most probably because of early recognition. The homozygous C282Y mutation in the HFE gene is responsible for most cases of hereditary hemochromatosis, although other much rarer mutations in other genes have been recently identified. Progressive iron overload not only causes liver cirrhosis but also triggers development of a characteristic arthropathy. Bony swelling with intermittent arthritis of the second and third metacarpophalangeal joints is typical as well as occurrence of chondrocalcinosis in wrists and knee joints. The therapy of choice is excess iron removal by phlebotomy. Treatment usually prevents or even reverses liver damage but does not alter the course of hemochromatosis arthropathy.

264. Distribution of Haemochromatosis Arthropathy. High Ankle and Midfoot Prevalence; a Diagnostic Clue?

264. Distribution of Haemochromatosis Arthropathy. High Ankle and Midfoot Prevalence; a Diagnostic Clue?

AB0979 A clinical and radiographic study comparing hand involvement in idiopathic osteoarthritis and hemochromatosis arthropathy

BackgroundHand osteoarthritis (HOA) can result from different conditions. Most known is idiopathic HOA, but there are also secondary forms due to metabolic diseases. Hereditary hemochromatosis (HH) arthropathy is the most...

VCAM-1 serum levels are associated with arthropathy in hereditary haemochromatosis

ObjectivesThe aim of this study was to assess the role of vascular adhesion molecule 1 (VCAM-1) in patients with hereditary haemochromatosis (HH) with or without arthropathy.MethodsSera from a large cross-sectional...

Erosive and inflammatory joint changes in hereditary hemochromatosis arthropathy detected by low-field magnetic resonance imaging

The aim of the article is to describe and characterize the hemochromatosis arthropathy of the hand by low-field MRI in symptomatic and asymptomatic patients. Forty-nine patients with hereditary hemochromatosis (37 with and twelve without arthropathy) were examined clinically and by low-field MRI of the hands. The examination showed heterogeneous degenerative and inflammatory joint changes such as erosions (in 84% of all symptomatic patients), synovitis (77%), bone marrow edema (38%), subchondral cysts (30%), tenosynovitis (30%), joint space narrowing (73%) and osteophytes (59%) including hook-shaped osteophytes at MCP joints (32%). Mild joint changes were also seen in a lower percentage of asymptomatic patients. This is the first larger study addressing the joint changes of the hand in hereditary hemochromatosis using low-field MRI. Our study emphasizes the inflammatory and destructive character of the arthropathy besides the well-known degenerative joint changes described in conventional X-ray. The impact of joint changes in asymptomatic patients deserves further investigation.

Idiopathic hand osteoarthritis vs haemochromatosis arthropathy--a clinical, functional and radiographic study

Haemochromatosis arthropathy is a secondary OA and the most frequent and earliest clinical presentation of hereditary haemochromatosis (HH). The aim of this study was to perform a direct clinical, functional and radiographic comparison with idiopathic hand OA (HOA) to unravel important differences between these clinical entities. In total, 299 patients (141 with HH arthropathy of the hands and 158 patients with idiopathic HOA) were recruited. Structured clinical assessment including hand function tests, as well as hand radiographs with scoring according to Kellgren-Lawrence, were carried out in all patients. HH arthropathy and HOA differed significantly: patients with HH arthropathy were younger and predominantly male as compared with HOA. In males but not females, HH arthropathy led to an earlier start of symptoms than in HOA. Patients with HOA had more tender joints and worse hand function than patients with HH arthropathy, although subjective measures of joint pain and function were similar. MCP and wrist joint involvement was more frequent and severe in HH arthropathy, while HOA patients more frequently had degenerative changes in the first CMC as well as PIP and DIP joints. HH arthropathy and idiopathic HOA differ significantly in terms of epidemiology, localization, severity of symptoms and radiographic changes.

Diagnostic radiographique d’un rhumatisme des mains et des poignets

Hand and wrist are the most frequent target of a large pannel of arthritis. The radiological diagnostic is often difficult at an early stage. The first radiological sign to be used is the presence of marginal bone erosions which is the hallmark of erosive inflammatory arthritis such as rheumatoid arthritis and psoriatic arthritis and, less commonly, gout. Marginal erosions occur at sites where intra-articular bone is not protected by an overlying hyaline cartilage. Presence of bone proliferation in association with marginal erosion or at enthesitic sites are the hallmark of spondylarthropathies, mainly psoriatic arthritis at the hand and wrist since it is lacking in rheumatoïd arthritis. Type of joint space narrowing is another important sign since diffuse joint space narrowing is very suggestive of inflammatory arthritis while focal joint space narrowing is suggestive of osteoarthritis and metabolic disorders. In the absence of marginal erosions, the radiological appearance is often suggestive of a degenerative disease with osteophytes and subchondral sclerosis. In such cases, distribution of the abnormal joints is a key sign since osteoarthritis predominates in the interphalangeal joints while CCPD arthropathy and hemochromatosis arthropathy are more marked in the metacarpophalangeal joints.

Hereditary hemochromatosis is characterized by a clinically definable arthropathy that correlates with iron load

To determine the frequency and character of arthropathy in hereditary hemochromatosis (HH) and to investigate the relationship between this arthropathy, nodal interphalangeal osteoarthritis, and iron load. Participants were recruited from the community by newspaper advertisement and assigned to diagnostic confidence categories for HH (definite/probable or possible/unlikely). Arthropathy was determined by use of a predetermined clinical protocol, radiographs of the hands of all participants, and radiographs of other joints in which clinical criteria were met. An arthropathy considered typical for HH, involving metacarpophalangeal joints 2-5 and bilateral specified large joints, was observed in 10 of 41 patients with definite or probable HH (24%), all of whom were homozygous for the C282Y mutation in the HFE gene, while only 2 of 62 patients with possible/unlikely HH had such an arthropathy (P=0.0024). Arthropathy in definite/probable HH was more common with increasing age and was associated with ferritin concentrations>1,000 μg/liter at the time of diagnosis (odds ratio 14.0 [95% confidence interval 1.30-150.89], P=0.03). A trend toward more episodes requiring phlebotomy was also observed among those with arthropathy, but this was not statistically significant (odds ratio 1.03 [95% confidence interval 0.99-1.06], P=0.097). There was no significant association between arthropathy in definite/probable HH and a history of intensive physical labor (P=0.12). An arthropathy consistent with that commonly attributed to HH was found to occur in 24% of patients with definite/probable HH. 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.

Validation of a radiographic scoring system for haemochromatosis arthropathy

BackgroundArthropathy is one of the earliest and most common manifestations of hereditary haemochromatosis with a significant impact on quality of life. Although its radiographic features are well known, there is...

Asymmetrical hemochromatosis arthropathy in a patient with a history of poliomyelitis

Herein, we report a case of a 67-year-old man with hereditary hemochromatosis and a history of poliomyelitis that had caused a paresis of the right arm. Hemochromatosis-associated arthropathy developed in all but the paretic limb. X-ray and MRI revealed degenerative, massive inflammatory and destructive changes in the joints of the non-paretic hand only. These findings argue for the contribution of physical exposure and non-mechanical factors to the development of the hemochromatosis arthropathy.

Synovial immunopathology in haemochromatosis arthropathy

BackgroundHereditary haemochromatosis (HH) is a common autosomal recessive inherited disorder that frequently causes arthritis. The pathophysiology of musculoskeletal involvement is, however, unclear.ObjectiveTo analyse synovial tissue obtained at surgery from patients...