Haemochromatosis and exercise related joint pains

Idiopathic haemochromatosis is an inherited disorder of iron metabolism in which excess iron absorption leads to tissue damage associated with a characteristic arthropathy. It is an uncommon but important cause of joint pains in middle age, and early diagnosis and treatment can reduce the long term illnesses and premature death associated with other complications of the disease.¹ We describe two cases of haemochromatosis in patients who presented with exercise related joint pains that were initially attributed to their running but were subsequently found to be the presenting symptoms of haemochromatosis. Earlier diagnosis might have prevented their subsequent irreversible joint damage.

Case reports

Case 1

A 51 year old woman who was a recreational runner presented with a five year history of pain in the middle of both feet. An acute ankle sprain 10 years before had not responded to conservative treatment, and she had not been given a clear diagnosis for her ongoing functional instability and persistent exercise related pain. At presentation to the sports clinic she gave a more recent history of back pain, pain in both sides of her hip, and pain in both metacarpals; she had had increasing difficulty with her grip over the previous two years because of aching and stiffness of her second and third metacarpals. Her brother also had similar symptoms which had not been investigated; he was later confirmed as having haemochromatosis. The patient had no other symptoms or signs of chronic liver disease or endocrine disturbance. She did, however, have soft tissue swelling over the affected metacarpals, some reduction in internal rotation of both hips, and painful, stiff subtalar joints.

The pattern of affected joints and the family history prompted further investigation. She had a serum ferritin concentration of 1087 μg/l, with normal results in liver function tests and a normal glucose concentration, full blood count, and erythrocyte sedimentation rate. Plain radiographs showed degenerative changes in the hands, with hooked osteophytes at the second and third metacarpals (fig 1) and at both subtalar and talonavicular joints, as well as minor degenerative changes in both hips (fig 2 (top)). She was referred to a haematologist, who started regular venesection. Her joint pains and arthropathy continued despite treatment, with rapid progression of her hip osteoarthritis (fig 2 (bottom)). A year later she was awaiting bilateral total hip replacements.

Figure 1.

Hand radiograph in case 1 showing degenerative changes at second and third metacarpals bilaterally with hooked osteophytes

Figure 2.

Radiograph in case 1 showing degenerative change at hip joints at presentation (top) and 18 months later (bottom)

Case 2

A 34 year old man who was a keen road runner presented with a short history of pain in the right groin after running more than 2 km. Clinical examination and plain x ray films established a diagnosis of unilateral osteoarthritis of the hip, and he was advised to modify his exercise habits and reduce his running. He was noted at the time to have marginally raised enzyme abnormalities in liver function tests. The following year he returned with pain and tenderness over the second and third metacarpophalangeal joints of his right hand. Two years later he developed pains in both shoulders.

At this stage clinical suspicion was aroused by the persistent nature and widespread distribution of symptoms in a man of this age with early osteoarthritis. His ferritin concentration was 4599 μg/l. Further assessment showed mild hepatomegaly and persistently increased liver function, with early fibrosis and heavy iron staining (but no cirrhosis) on liver biopsy. There was no family history of haemochromatosis. After two years of treatment with venesection, liver function tests gave normal results and ferritin concentration was normal but the osteoarthritis in his hip had progressed and become bilateral, with unremitting pain and clinically significant disability. Two years later, seven years after the onset of his symptoms and at the age of 41, he had bilateral total hip replacements.

Discussion

Haemochromatosis is the most common inherited metabolic disorder in the Western world. It has an autosomal recessive pattern of inheritance and affects 1 in 250 of the northern European population, with up to 10% of people carrying the gene. Inheritance of the disease has long been associated with the tissue type HLA A3, and HLA-H was recently identified as a candidate gene.² A specific mutation of this gene, C282Y, was present in 83% of 178 cases of haemochromatosis and has a geographical distribution that coincides with that of haemochromatosis.³ Genetic typing is now being used to aid clinical diagnosis and has been proposed as a tool for population screening.³,⁴

Haemochromatosis is a disorder of iron absorption and storage within the body, with a characteristic pattern of tissue damage resulting from excess iron deposition—haemosiderosis. Derangement of liver function may progress to fibrosis, cirrhosis, and ultimately liver failure. In tissues such as the synovium iron deposition and radiological evidence of arthropathy or joint distribution do not seem to be correlated,⁵ and the role of haemosiderosis in the mechanism of haemochromatotic arthropathy is debatable.⁶,⁷

The clinical presentation of haemochromatosis is variable and not confined to the classic triad of cirrhosis, diabetes, and skin pigmentation (the so called bronze diabetic patient). Patients are predominantly men (ratio of 9 to 1) and usually present between the ages of 40 and 60 years with lethargy, weakness, and sleep disturbance or with diabetes or gonadal failure, but early symptoms are often subtle and easily overlooked. There may be a family history of haemochromatosis or its complications (box 1).

Haemochromatosis is diagnosed on the basis of excess iron stores. Iron stores are best calculated by first measuring serum ferritin concentration, which accurately reflects total body iron stores and is raised in the disease (usually >1000 μg/l; normal values are <330 μg/l in men and <120 μg/l in women). Serum iron concentration and transferrin saturation are also raised. Screening for cases of suspected haemochromatosis should include a careful history, clinical examination, and investigations (box 2). Referral to a haematologist will then allow further assessment, which usually includes magnetic resonance imaging of the liver, liver biopsy, and HLA tissue typing. First degree relatives should also be screened. The treatment for haemochromatosis is regular venesection to lower the body’s iron stores. This is initially every week, but maintenance treatments are usually required only 4-8 times a year. Niederau et al reported that life expectancy was normal among 251 patients (mean follow up 14 years) who began treatment before the development of diabetes or cirrhosis and that hepatic fibrosis could be improved with iron removal.¹

Arthropathy was first recognised in 1964⁸ and affects as many as 64% of patients with haemochromatosis.⁹ Although arthropathy was initially considered to be a late feature of the disease,¹⁰,¹¹ it has been increasingly recognised as an early manifestation and the predominant clinical factor affecting the quality of life of patients with haemochromatosis.¹² Niederau et al reported that arthralgia was present in 45% of symptomatic cases at the time of diagnosis,¹ and Faraawi et al found it to be the most common clinical feature at the time of diagnosis, occurring in 16 of their 25 patients.⁹ These patients estimated that their symptoms of arthralgia had been present for at least three years before a diagnosis was established. Haemochromatotic arthropathy without other features of the disease has also been reported.¹³,¹⁴

The characteristic feature of haemochromatotic arthropathy is involvement of the second and third metacarpals, which are often stiff, painful, and mildly tender, with small cysts and hooked osteophytes developing at the metacarpal heads (fig 1). The arthropathy is degenerative, rather than inflammatory (erythrocyte sedimentation rate is typically normal), and can lead to extensive joint destruction, with as many as a third of patients whose hips are affected requiring joint replacement.⁷ Deposition of calcium pyrophosphate with chondrocalcinosis is found in 36-72% of cases and commonly affects the wrists, knees, hips, and symphysis pubis (fig 3).⁹,¹⁰,¹⁵ These patients may have episodes of acute, inflammatory pseudogout from such deposition. Thus, the musculoskeletal manifestations of haemochromatosis can present in various ways and are often the first symptoms of the disease (box 3).

Figure 3.

Knee radiograph showing chondrocalcinosis in joint space

The symptoms of arthropathy improve in up to 30% of patients after removal of excess iron; they worsen in 20% and are unaffected by treatment in the rest.¹ The observation that arthralgia presents as commonly among patients with and without cirrhosis (45% v 44%) and does not relate to the amount of mobilisable iron,¹,⁹ suggests that it is independent of disease duration and may be an early feature of the disease. The importance of establishing the underlying cause of arthralgia in previously undiagnosed cases of haemochromatosis is to enable treatment to be started early.

Our two cases show that haemochromatosis may present with arthropathy without the more recognisable features of the disease and that the diagnosis is easily overlooked in patients presenting with exercise related joint pains if symptoms are attributed solely to their exercise and sporting activities. We have diagnosed haemochromatosis early in five other patients who presented with exercise related joint pains but without the more typical haemochromatotic features that eventually developed in these two cases. Screening for the disease is simple, and early diagnosis and treatment can prevent the development of serious, irreversible complications.

Box 1.

—Complications of haemochromatosis

Hepatic—increased activity of liver enzymes, fibrosis, cirrhosis

Endocrine—diabetes, hypogonadism

Cardiac—myopathy, arrhythmia

Musculoskeletal—osteoarthritis, arthropathy from calcium pyrophosphate deposition

General—skin pigmentation, lethargy, and malaise

Box 2.

—Screening for suspected haemochromatosis

Family history

Clinical signs of liver disease, diabetes

Serum ferritin concentration

Liver function tests, urine analysis, blood glucose concentration

Radiography of affected joints

Box 3.

—Musculoskeletal signs of haemochromatosis

Vague aches and pains

Early onset osteoarthritis

Deposition of calcium pyrophosphate—chondrocalcinosis, acute pseudogout

Stiffness and arthralgia in second and third metacarpals