Hereditary haemochromatosis presenting to rheumatology clinic as inflammatory arthritis

Abstract

Hereditary haemochromatosis (HH) is the most commonly identified genetic disorder in Caucasians. HH has a wide variety of clinical manifestations. As such, the presenting complaint in new diagnoses of HH can be non-specific such as fatigue; however, joint symptoms such as arthralgia are also common. These joint symptoms closely mimic the features of other musculoskeletal diseases such as rheumatoid arthritis (RA). Early diagnosis of HH is key to prevent long-term irreversible complications such as liver damage, diabetes and degenerative joint disease. We present a case of HH which was initially suspected to be early RA, with ultrasound findings of active synovitis. High clinical suspicion, a raised serum ferritin followed by genetic testing for C282Y mutation confirmed the diagnosis of HH. The synovitis responded to corticosteroids and was suspected to be due to pseudogout a known complication of HH. Early diagnosis and treatment resulted in a favourable outcome.

Background

Hereditary haemochromatosis (HH) is an autosomal recessive condition in which progressive iron overload causes organ damage including arthropathy, fatigue, liver disease, bronze diabetes and cardiomyopathy.¹ It is the most commonly identified genetic disorder in Caucasians, with an approximate prevalence of 1 per 250 individuals.² While the clinical manifestations are wide, disease presentation is commonly insidious, with non-specific symptoms such as fatigue, mood disturbance and adynamia.³ Arthralgia or joint pain is also a common presenting complaint with types of arthropathy seen in HH including secondary chondrocalcinosis also known as calcium pyrophosphate crystal deposition (CPPD), pseudogout and secondary osteoarthritis (OA).⁴

The genetics of HH involve mutations of the HFE gene located on chromosome 6, of which C282Y is the most common.⁵ Prevalence in Caucasians of the C282Y mutation is approximately 0.5% and the majority of patients who receive a clinical diagnosis of HH are homozygous for the C282Y HFE mutation.^6–8 Another HFE gene mutations also exist, including H63D mutations; however, these are not usually associated with iron overload.⁹ Penetrance of the C282Y mutation is an area of controversy and ongoing research, with very low phenotypic expression of the C282Y mutation in women, and moderate expression in men, possibly due to a protective effect of menopause.^{10 11}

Approximately two-thirds of patients with HH are affected by arthropathy, with OA-like symptoms being the most frequently encountered in clinical practice.¹² Classically HH causes degenerative changes in the second and third metacarpophalangeal (MCP) joints; however, a wide variety of clinical presentations are seen in clinical practice including symmetrical bilateral joint involvement, large and small joint involvement, and chondrocalcinosis.^{13 14}

We present a case of HH which presented as a case of suspected early rheumatoid arthritis (RA).

Case presentation

A 52-year-old post-menopausal woman was referred to the rheumatology outpatient clinic by her general practitioner due to a 3-month history of tender, swollen joints in the hands, wrists and ankles, as well as fatigue. She first presented at the age of 47 with arthralgia without any obvious cause or concurrent illness. After initial investigations by a rheumatologist she was diagnosed as having osteoarthritis and was discharged.

Over time, she noticed intermittent joint swelling mainly affecting her hands and early morning stiffness lasting up to an hour. Naproxen or tramadol on an as required basis did not alleviate her joint symptoms. Her activities of daily living were severely restricted, especially exacerbated by stiffness affecting her left hip.

Having previously been a professional ice skater, she continued with the sport as a hobby before having to give it up completely due to her symptoms. In addition to her arthralgia, she developed symptoms of sciatica for which she sought treatment from a chiropractor, which did not improve her pain.

A family history revealed no history of inflammatory arthropathies; however, her mother and brother were affected by osteoarthritis. In terms of a social history, she lives a healthy lifestyle doing light exercise several times a week, and has two healthy adult children. She has never smoked, drinks less than 8 units of alcohol per week and does not binge-drink.

Physical examination of her hands showed obvious signs of Heberden’s and Bouchard’s nodes, and bilateral subluxation of the carpometacarpal joints (see figure 1). On examination, both her right and left MCPs and wrist joints were tender and swollen. Examination of her left hip revealed restricted movements, and tenderness to palpation. Examination of the right and left knee joints demonstrated crepitus on passive movement. Finally, incidentally, hypermobility affecting the elbows, shoulders, lower back and ankles was detected along with pes planus.

Figure 1.

Photographs of the hands and wrists with mild swelling of the metacarpophalangeals and wrist joints bilaterally as well as Heberden’s and Bouchard’s nodes bilaterally.

During her initial assessment in the rheumatology clinic, an ultrasound scan (USS) was performed on the joints of her hands and wrists, with measurement of Grey scale and power Doppler. In this case, the USS revealed small osteophytes affecting the second and third MCP joints bilaterally, with Grey scale 2+ and power Doppler 2+ suggesting active synovitis in the second and third MCP joints bilaterally (see figure 2).

Figure 2.

Ultrasound scan of the right metacarpophalangeal 2, 3 and 5, which showed power Doppler signal 2+ and Grey scale 2+ consistent with active synovitis.

Plain radiographs of her hands demonstrated reduced joint space of the second and third MCP joints bilaterally without osteophytes as well as changes in the Distal interphalangeal joints (DIP) and Proximal interphalangeal (PIP) joints consistent with age-related degeneration. Plain radiographs of her feet demonstrated changes in the first metatarsophalangeal joints bilaterally consistent with age-related degeneration. Importantly, there was no observed evidence of chondrocalcinosis in any of the joints of the hands, feet or knees on any of the initial plain radiographs (see figure 3).

Figure 3.

Plain radiographs of the hands and feet showing degenerative changes including reduced joint space in the second and third metacarpophalangeals bilaterally without osteophytes, degenerative changes affecting the distal interphalangeal joints and proximal interphalangeal joints (PIPs), degenerative changes in the first metatarsophalangeals bilaterally and no evidence of chondrocalcinosis.

While awaiting the results of her blood tests, she was given 80 mg of Kenalog (triamcinolone acetonide) as an intramuscular injection, as treatment for suspected early RA.

After initial assessment, there was a high degree of clinical suspicion that this could represent a diagnosis other than RA. Due to the involvement of the second and third MCP joints, HH was specifically considered as a differential, and iron studies were requested.

Her initial blood tests including full blood count, liver function tests, glucose and inflammatory markers were normal. She was negative for rheumatoid factor and anti-cyclic citrullinated peptide (CCP) antibody.

Due to her ethnicity, and significant degenerative changes observed on physical examination and plain radiographs, especially with involvement of the second and third MCP joints, alternative causes such as HH were considered. Iron studies were requested in addition to her other routine investigations, which showed a significantly elevated ferritin of 963.3 μg/L (normal range 13–150) with raised iron 42.0 μmol/L (normal range 5.8–34.5) and raised transferrin saturation 79.2% (normal range 15%–45%).

As part of the subsequent workup for HH, an USS of her liver was performed which was reported as normal, and subsequent genotyping demonstrated homozygosity for C282Y mutation confirming the diagnosis of HH and not RA.

Outcome and follow-up

After confirming the diagnosis of HH, the patient was followed-up in outpatient clinic 3 months later. On review, she reported improvement in symptoms including pain, swelling and stiffnessof all her joints after having received the intramuscular corticosteroid injection. A repeat USS in clinic showed similar findings in terms of Grey scale and osteophytes, but crucially, no power Doppler signal was detected indicating an absence of inflammation, potentially due to the effects of the corticosteroids. Despite the improvement, she continued to report of mild ongoing intermittent swelling affecting her MCPs and wrists joints, colchicine was prescribed on an as required basis to be used during acute episodes.

It is suspected that her symptoms are due to a combination of osteoarthritis and pseudogout, the latter of which is associated with HH. However, we were not able to obtain any synovial fluid for crystal visualisation to confirm the diagnosis of pseudogout.

She was referred to the local haematology unit and commenced on fortnightly phlebotomy treatment for her HH. Following several treatments with venesection her iron levels returned to normal levels. She continued to suffer from chronic pain requiring increasing amounts of analgesia including opioids. As such, she had bilateral hip replacements which dramatically improved her arthralgia. She was able to come off the opioids, and now only takes regular analgesia when required. Thanks to treatment she is now able to go back to regular ice skating.

Discussion

This case highlights the importance of HH closely mimicking RA as well as the potential diagnostic pitfalls when interpreting power Doppler synovitis on USS in the context of an undifferentiated arthropathy. Furthermore, this case highlights how the use of musculoskeletal USS in routine rheumatological practice, especially in atypical cases, can help to differentiate diseases such as HH in clinical practice.

Due to the known existent of osteoarthritis in this patient, it was difficult to differentiate the arthralgia caused by HH from early RA. Further complicating the clinical picture, the USS showed evidence of active synovitis which is typically seen in early RA; however, in hindsight it is thought this may have been due to inflammatory osteoarthritis or pseudogout, both of which can be seen with HH.

Pseudogout is known to be associated with HH, but X-rays of her hands, feet and knees showed no evidence of chondrocalcinosis, though synovial fluid with evidence of crystals would be needed to confirm the diagnosis. Furthermore, the X-ray of her hands showed no evidence of the typical hooked osteophytes in MCP 2 and 3 seen in HH, only mild reduction in joint space which can occur in RA.

As such the precise cause of the joint inflammation seen on power Doppler in this patient remains unknown, but possible disease processes include inflammatory OA, CPPD and direct iron deposition which have previously been shown on electron microscopy studies.¹⁵

There have been several other case reports of HH arthropathy associated with power Doppler signal on USS.^{16 17} In one case, a 40-year-old Caucasian man was found to have power Doppler signal affecting the index and middle MCP joints as well as hooked osteophytes of the index and middle MCPs on X-ray of the hands.¹⁶ In another case, a patient with similar findings of second and third MCP involvement was mistakenly diagnosed as RA and treated with disease-modifying antirheumatic drugs until a diagnosis of HH was made incidentally when iron studies were requested for fatigue.¹⁷

Overall, it is easy to see how in this case, the diagnosis of HH could have been missed and a false diagnosis of seronegative RA made instead. This patient did not have other classic signs of HH often seen in textbooks and taught in medical school such as anaemia, deranged liver transaminases, diabetes, skin pigmentation and heart failure, nor did she have a family history of HH or hooked osteophytes seen on X-ray. However, early diagnosis with early treatment helped to prevent complications in both the patient and other affected family members. As such, a high degree of clinical suspicion coupled with ultrasound imaging was imperative in this case.

Learning points.

• Hereditary haemochromatosis can present with a similar clinical phenotype to inflammatory arthropathies such as early rheumatoid arthritis.

• Doppler synovitis on USS is found in haemochromatosis and could be misinterpreted as early rheumatoid arthritis.

• Early diagnosis of hereditary haemochromatosis and early treatment can prevent multiple complications associated with this condition.

Data availability statement

Data is available upon reasonable request to the corresponding author.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).