BMJ 2011; 343:d6197 doi: 10.1136/bmj.d6197 (Published 14 October 2011)
Cite this as: BMJ 2011; 343:d6197
[Link to free full-text BMJ Endgames article PDF] [PubMed® abstract]
Endgames
Picture Quiz
Rusty joints
van Onna M, van Asbeck BS, Jacobs JWG
Correspondence to: M van Onna mariekevanonna@hotmail.com
[EXCERPTS]
A 47 year old white man presented to the outpatient clinic with progressive pain and stiffness of hands and feet of five years duration. During this time he once experienced swelling of the knuckles of his right hand that resolved spontaneously within a week. Diclofenac 50 mg twice daily had not been effective. A year ago ankle osteoarthritis had been diagnosed arthroscopically. He did not smoke or drink alcohol. His father, who had diabetes, also had painful joints. On examination, he was noted to be tanned, with a body mass index of 27. He had subtle arthritis of the second and third metacarpophalangeal joint of the left hand and third metacarpophalangeal joint of the right hand, Heberden’s nodes of several distal interphalangeal hand joints, and crepitus of ankle and knee joints bilaterally. The liver was palpable 3 cm below the right costal margin. Otherwise, physical examination was unremarkable. Laboratory tests and radiographs were ordered.
Fig 1Radiograph of hands and wrists
Questions
1 What are the differential diagnoses for this patient’s joint problems?
2 What abnormalities can be seen on the radiograph?
3 What is the most likely clinical diagnosis?
4 How is this clinical diagnosis confirmed?
5 How can this condition be treated?
Answers
1 What are the differential diagnoses for this patient’s joint problems?
Short answer
The main differential diagnoses are primary osteoarthritis, secondary osteoarthritis as a result of haemochromatosis, rheumatoid arthritis, psoriatic arthritis, and crystal arthropathies (calcium pyrophosphate deposition disease and chronic gout).
Long answer
At first sight our patient seemed to have signs and symptoms of primary (idiopathic) osteoarthritis (Heberden’s nodes, crepitus of knee joints). However, primary osteoarthritis cannot be the cause of all his joint problems.
Firstly, his second and third metacarpophalangeal joints and his ankles are affected, and these joints are rarely affected by primary osteoarthritis. Secondly, one episode with swelling could suggest subtle but persistent arthritis, although swelling of osteoarthritic joints may occur. Thirdly, polyarticular primary osteoarthritis is unusual in a relatively young man. Secondary osteoarthritis therefore seems more likely.
The patient’s history is not compatible with long standing psoriatic arthritis or rheumatoid arthritis. Symmetrical involvement of metacarpophalangeal joints is often seen in rheumatoid and psoriatric arthritis, and the absence of psoriasis does not fully exclude psoriatric arthritis. However, proximal interphalangeal joints, wrists, and small joints of the feet, which were not affected in our patient, are commonly affected in these diseases. Furthermore, both types of arthritis cause overt signs of arthritis, which were not present in our patient.
Osteoarthritis with deposition of calcium pyrophosphate and chronic calcium pyrophosphate crystal inflammatory arthritis usually occur in older people and are often, but not always, accompanied by episodes of acute calcium pyrophosphate crystal arthritis (pseudogout). The same applies to gout, which more often affects joints other than those of the hands and is eventually associated with tophi.
This combination of signs (slight swelling) and symptoms (pain) in the second and third metacarpal joints in a man in his 40s is typical of hereditary haemochromatosis arthropathy. The most common arthritic manifestations of this disease include pain and minimal joint inflammation of the small joints of the hands, particularly the second and third metacarpophalangeal joints, but it may progress to affect the large joints and is clinically difficult to distinguish from osteoarthritis. Longstanding hereditary haemochromatosis may result in calcium pyrophosphate deposition in joints and episodes of acute calcium pyrophosphate crystal arthritis, especially of wrists and knee joints. Other clues in this case are that his father had diabetes and joint symptoms, both of which may be related to hereditary haemochromatosis, which is a familial disease. Furthermore, he had slight hepatomegaly and his skin was tanned, perhaps because of hyperpigmentation as a result of hereditary haemochromatosis (“bronze skin”). Hyperpigmentation and diabetes are findings in end stage disease, however.
2 What abnormalities can be seen on the radiograph?
Short answer
There is narrowing of the joint spaces of the metacarpophalangeal and proximal interphalangeal joints, with hook-like osteophytes of the metacarpophalangeal joints, which are not compatible with primary osteoarthritis.
Fig 2 Radiograph of hands and wrists. The arrow indicates an example of a hook-like osteophyte
Long answer
The radiographs show narrowing of the joint spaces of the metacarpophalangeal and proximal interphalangeal joints with hook-like osteophytes (fig 2). Minor osteophytes can be seen at the second and third distal interphalangeal joint of the right hand. The lack of erosions argues against longstanding rheumatoid arthritis, psoriatric arthritis, and gout. Chondrocalcinosis, which is indicative of deposition of calcium pyrophosphate, is not seen. The abnormalities are not compatible with primary osteoarthritis, but the hook-like osteophytes are pathognomic for iron overload disease, which is associated with a variety of genetic and acquired conditions.
3 What is the most likely clinical diagnosis?
Short answer
Hereditary haemochromatosis.
Long answer
The most likely clinical diagnosis is hereditary haemochromatosis. In healthy people, iron absorption from the gut is tightly controlled and dependent on the body’s iron needs. Hereditary haemochromatosis refers to a group of heritable disorders that are characterised by excessive intestinal iron resorption and release from macrophages, which lead to iron overload. The disease is caused by a variety of mutations in genes that regulate iron metabolism. Around 80% of patients with hereditary haemochromatosis of northern European descent are homozygous for the Cys282Tyr mutation in the HFE gene. In people of northern European descent, the prevalence of homozygosity for Cys282Tyr is 4-7 per 1000 subjects; 12-25% of these homozygous people eventually develop iron overload disease.
4 How is this clinical diagnosis confirmed?
Short answer
The first step is to confirm iron deposition disease by determining serum ferritin concentrations and plasma transferrin saturation. If these are raised, analysis of the HFE gene should be performed.
Long answer
The first step is the confirmation of iron overload. Serum ferritin values reflect the body’s storage of iron. Normal serum concentrations virtually rule out iron overload. However, raised ferritin values (>200 µg/L for women and >300 µg/L for men) can be caused by a variety of conditions (such as inflammation, high alcohol consumption, metabolic syndrome, liver cell necrosis). Next transferrin saturation should be tested after overnight fasting. If transferrin saturation is greatly increased (>45% for women, >50% for men), iron overload is likely and genetic testing for haemochromatosis should be performed. Haemochromatosis is a generalised disease, so once the diagnosis is confirmed a complete investigation of possibly effected target organs should be performed. Tests include fasting blood glucose and liver function tests in all patients, and—depending on the clinical features—patients should be screened for cardiac disease (using electrocardiography and echocardiography) and hypogonadism (thyroid stimulating hormone and testosterone).
5 How can this condition be treated?
Short answer
Phlebotomy is the mainstay of treatment. Musculoskeletal symptoms may be treated with analgesics and non-steroidal anti-inflammatory drugs (NSAIDs).
Long answer
Phlebotomy is the mainstay of treatment in haemochromatosis, and early phlebotomy can prevent excess mortality caused by iron deposition in parenchymal tissue. A high index of suspicion is therefore necessary.
Nowadays, the classic full blown presentation of longstanding haemochromatosis—liver cirrhosis, bronzed skin, diabetes, joint arthropathy and inflammation, and heart disease in a middle aged white man—is rarely seen. Arthritis and arthropathy are among the most common and early manifestations. Although most joints can be affected, the second and third metacarpophalangeal joints are the most common. At a structured physical examination by a rheumatologist in a cohort of patients with blood test results that were compatible with iron overload, half of the patients had bony swollen second and third metacarpophalangeal joints.
The mechanisms by which iron overload produces arthropathy are not well understood. To our knowledge, arthropathy has not been studied in animal models of haemochromatosis. Morphological studies on cartilage and synovium of joints of patients with advanced disease undergoing joint replacement surgery show advanced degenerative changes of the articular cartilage and bone, together with deposition of haemosiderin, calcium pyrophosphate dehydrate, and apatite-like crystals. Synovial tissue from joints affected by haemochromatosis resembles that from joints with primary osteoarthritis. Both show low grade synovitis, but infiltration by macrophages and neutrophils is more prominent in haemochromatosis. Considering the histological similarity with primary osteoarthritis, it is not surprising that phlebotomy usually has little effect on existing arthropathy in haemochromatosis. Presumably, phlebotomy prevents further joint damage and ensuing signs and symptoms by precluding further iron storage in the joint. This emphasises the importance of an early clinical diagnosis, based on recognition of the particular pattern of signs and symptoms. The symptoms of existing joint damage are treated by analgesics and non-steroidal anti-inflammatory drugs. In cases of complicating calcium pyrophosphate deposition disease with acute arthritis, colchicine and non-steroidal anti-inflammatory drugs are usually effective.
Patient outcome
Our patient had iron overload (ferritin 1796 µg/L, reference range 25-250; transferrin saturation 89%, 25-60%) and was homozygous for the Cys282Tyr mutation. Hereditary haemochromatosis was diagnosed. Apart from arthropathy and hepatomegaly (with normal liver function tests), he had no clinical symptoms of iron deposition. When asked he reported that he regularly sunbathed, so in the absence of other features of established disease, this is a more likely explanation than iron overload for his hyperpigmented skin. Treatment with phlebotomy was started. As expected, his joint problems remain.
© 2011 BMJ Publishing Group Ltd.
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