Haemochromatosis arthropathy

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Hereditary haemochromatosis is a systemic iron-loading disorder caused most often by HFE C282Y homozygosity. Its arthropathy is an important diagnostic clue because joint symptoms may precede liver, endocrine or cardiac manifestations. The classic distribution is the second and third metacarpophalangeal joints, with wrists, hips, knees and ankles also affected. Radiographs may show hook-like osteophytes at metacarpal heads, joint-space narrowing and chondrocalcinosis.

The joint phenotype combines a chronic osteoarthritis-like process and susceptibility to calcium-pyrophosphate crystal arthritis. Neither a high ferritin nor chondrocalcinosis alone establishes hereditary haemochromatosis. Ferritin rises with inflammation, alcohol-related or metabolic liver disease and malignancy; transferrin saturation and, where appropriate, HFE testing identify inappropriate iron loading. People without the diagnostic C282Y-homozygous biochemical pattern require specialist confirmation of tissue iron and exclusion of secondary causes.

Key points

Think haemochromatosis when osteoarthritis-like pain involves the second and third MCP joints, especially with hook osteophytes, wrist or knee chondrocalcinosis, ankle disease or early hip replacement.
The first biochemical pair is fasting or repeat transferrin saturation and ferritin: transferrin saturation detects inappropriate circulating iron availability, whereas ferritin is an acute-phase and liver-injury marker as well as an iron-store marker.
In an HFE C282Y homozygote, raised transferrin saturation plus ferritin above sex-appropriate thresholds can establish provisional iron overload; other genotypes generally need specialist evidence of hepatic iron on MRI or biopsy.
First-line disease-modifying treatment for confirmed iron overload in a suitable non-anaemic patient is therapeutic venesection, usually 400 to 500 mL weekly or fortnightly during induction.
The EASL induction ferritin target is about 50 micrograms/L without pushing lower; maintenance is usually 50 to 100 micrograms/L with individualised venesection intervals.
Venesection prevents or improves important systemic outcomes but established haemochromatosis arthropathy often persists, so joint-specific osteoarthritis and CPP management must continue.
A new hot joint still needs aspiration for Gram stain, culture and crystal analysis; chondrocalcinosis is not proof that current inflammation is sterile.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

HFE-related haemochromatosis

Autosomal-recessive HFE variants, most importantly C282Y homozygosity in people of northern European ancestry, reduce hepcidin signalling and cause excessive intestinal iron absorption over decades.

Non-HFE hereditary overload

Rare pathogenic variants affecting hepcidin, haemojuvelin, transferrin receptor 2 or ferroportin produce different ages and patterns of iron loading and need specialist genomic interpretation.

Secondary iron overload

Repeated transfusion, ineffective erythropoiesis, chronic liver disease and some haematological disorders elevate iron indices but are not HFE haemochromatosis and may require chelation rather than venesection.

Joint susceptibility

The severity of arthropathy correlates imperfectly with total iron burden; age, cartilage iron, CPP deposition, mechanical load and individual susceptibility contribute to the phenotype.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Inappropriately low hepcidin
Deficient hepcidin leaves ferroportin active on enterocytes and macrophages, increasing plasma iron delivery, transferrin saturation and ultimately non-transferrin-bound iron.
2
Parenchymal iron toxicity
Reactive iron promotes oxidative injury and fibrosis in liver, pancreas, pituitary, myocardium, skin and other tissues, explaining the preventable systemic complications.
3
Cartilage and crystal effects
Iron within synovium and cartilage may alter pyrophosphate metabolism and matrix repair, favouring calcium-pyrophosphate crystals, chondrocalcinosis and an osteoarthritis-like destructive process.
4
Characteristic structural pattern
Second and third metacarpophalangeal cartilage and wrists are disproportionately affected; hook-like osteophytes at metacarpal heads and joint-space loss provide a radiographic clue.
5
Incomplete joint reversibility
Venesection removes mobilisable body iron and protects organs but cannot reliably reverse established cartilage loss, osteophytes or CPP deposits, so joint symptoms may persist despite biochemical depletion.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Characteristic MCP disease

Pain, bony enlargement and reduced grip centred on MCP2 and MCP3, often without the florid synovitis of rheumatoid arthritis, is the most useful joint-distribution clue.

Hook osteophytes

Beak-like osteophytes projecting from the radial aspects of metacarpal heads, particularly at the second and third rays, support haemochromatosis arthropathy in the right biochemical setting.

Chondrocalcinosis phenotype

Linear cartilage calcification in wrists or knees and recurrent acute CPP attacks may be the presenting manifestation; disease at a relatively young age strengthens the metabolic signal.

Large-joint and ankle disease

Hip, knee and ankle degeneration can be severe or occur earlier than expected, sometimes leading to joint replacement before systemic haemochromatosis is diagnosed.

Systemic iron clues

Fatigue, bronze or grey skin, hepatomegaly, abnormal liver tests, diabetes, reduced libido, erectile dysfunction, amenorrhoea, cardiomyopathy or arrhythmia should prompt unified assessment.

Red flags requiring action

Exertional syncope, sustained palpitations, chest pain, breathlessness, oedema or heart failure can reflect iron-related cardiomyopathy or arrhythmia and requires urgent cardiac assessment.
Jaundice, ascites, encephalopathy, gastrointestinal bleeding or coagulopathy suggests advanced liver disease and needs same-day hospital evaluation.
Cirrhosis or advanced fibrosis confers hepatocellular-carcinoma risk even after iron depletion and requires an organised surveillance pathway.
Polyuria, polydipsia, weight loss, vomiting or altered consciousness may represent severe diabetes or ketoacidosis and is not simply fatigue from iron overload.
Fever with a hot swollen joint requires aspiration and culture; haemochromatosis-associated CPP disease does not exclude concurrent septic arthritis.
New hypogonadal symptoms, osteoporosis, pathological fracture, skin ulceration or rapidly progressive weakness suggests clinically important extra-articular organ involvement.
Ferritin above 1,000 micrograms/L, abnormal liver tests, hepatomegaly or substantial alcohol exposure increases the probability of advanced fibrosis and needs prompt specialist staging.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
First-line transferrin saturation and ferritinFirst stepFirst line
Why
Identify biochemical iron loading while distinguishing circulating iron excess from nonspecific hyperferritinaemia.
Interpretation and limitations
Repeat a borderline or discordant transferrin saturation under locally standardised conditions. EASL uses greater than 45% in women and greater than 50% in men with ferritin above 200 and 300 micrograms/L respectively as a biochemical trigger in the appropriate context.
02
HFE genotyping
Why
Confirm common hereditary haemochromatosis after compatible iron indices or in an appropriately counselled adult relative.
Interpretation and limitations
C282Y homozygosity plus the characteristic biochemical pattern supports HFE haemochromatosis. C282Y/H63D compound heterozygosity or a single variant has lower penetrance and should not be blamed for iron overload without phenotypic evidence.
03
FBC and haemoglobin
Why
Establish whether venesection is safe and detect an alternative explanation for fatigue.
Interpretation and limitations
Anaemia is not a feature of uncomplicated HFE iron loading and should trigger reconsideration. Check haemoglobin before each venesection and reduce frequency below 120 g/L or pause below 110 g/L under the treating protocol.
04
Liver profile and fibrosis assessment
Why
Stage the organ most commonly damaged and determine surveillance need.
Interpretation and limitations
Use liver enzymes, synthetic function, platelets and a validated non-invasive fibrosis pathway; ferritin above 1,000 micrograms/L or abnormal findings prompts specialist elastography, MRI or occasionally biopsy.
05
Liver MRI iron quantification
Why
Demonstrate and quantify hepatic iron when genotype is not diagnostic or secondary overload is possible.
Interpretation and limitations
In non-C282Y-homozygous patients with persistent high transferrin saturation and ferritin, hepatic iron on validated MRI helps confirm true overload and its distribution; biopsy is reserved for selected fibrosis or diagnostic questions.
06
Hand and symptomatic-joint radiographs
Why
Identify the characteristic structural distribution and alternative arthritis.
Interpretation and limitations
Look for MCP2 or MCP3 joint-space loss, radial hook osteophytes, subchondral sclerosis or cysts and wrist or knee chondrocalcinosis; radiographs support the joint phenotype but do not diagnose systemic iron overload.
07
Hot-joint aspiration
Why
Differentiate CPP crystal arthritis, gout and septic arthritis.
Interpretation and limitations
Send cell count, Gram stain, culture and polarised microscopy. Weakly positive rhomboid CPP crystals support an associated flare, but culture remains required when infection is plausible.
08
End-organ assessment
Why
Detect preventable complications and establish referral urgency.
Interpretation and limitations
At diagnosis assess glucose or HbA1c, liver status, symptoms and ECG for cardiac disease, gonadal function when clinically indicated and osteoporosis risk; use echocardiography or cardiac MRI for compatible symptoms or severe loading.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Calcium-pyrophosphate deposition disease

Idiopathic CPPD shares chondrocalcinosis and acute attacks; early or extensive CPPD and second or third MCP disease should trigger iron studies rather than being labelled primary CPPD.

Primary hand osteoarthritis

DIP, PIP and first-CMC nodes predominate in ordinary hand OA, whereas MCP2 and MCP3 involvement, hook osteophytes and wrist chondrocalcinosis favour haemochromatosis.

Rheumatoid arthritis

Symmetrical MCP pain and swelling overlap, but prolonged morning stiffness, persistent synovitis, erosions, RF or anti-CCP and absence of hook osteophytes support inflammatory arthritis.

Diabetic cheiroarthropathy

Limited joint mobility and waxy skin in diabetes can impair the hands but do not explain characteristic chondrocalcinosis, hook osteophytes or high transferrin saturation.

Other causes of hyperferritinaemia

Alcohol-related liver disease, metabolic dysfunction, inflammation, malignancy and cell injury can elevate ferritin without increased transferrin saturation or genetically mediated iron loading.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01First diagnostic priorityConfirm iron loading, not ferritin aloneFirst stepCharacteristic MCP or CPPD-pattern arthropathy, systemic features or a family history raises suspicion.

1Request transferrin saturation and ferritin together, with FBC, liver profile and CRP or clinical inflammation context; repeat discordant borderline results.
2If biochemical loading is present, arrange HFE testing with consent and ancestry-aware interpretation and review alcohol, metabolic liver disease, transfusions and haematological causes.
3Refer non-C282Y-homozygous or otherwise complex overload for hepatic MRI, fibrosis assessment and specialist diagnosis rather than inferring hereditary disease from ferritin.

02Systemic stagingDefine organ harm before routine joint careHereditary haemochromatosis or convincing iron overload is confirmed.

1Assess fibrosis risk, liver synthetic function, glucose, cardiac symptoms and ECG, endocrine and bone features and medicines or comorbidity affecting venesection.
2EscalationEscalate ferritin above 1,000 micrograms/L, hepatomegaly, abnormal liver tests, cardiac symptoms or decompensation promptly to the relevant specialist.
3Place advanced fibrosis or cirrhosis into a continuing hepatocellular-carcinoma surveillance pathway even after iron depletion.

03First-line iron depletionUse monitored therapeutic venesectionFirst lineConfirmed iron overload is present and haemoglobin and cardiovascular status allow phlebotomy.

1Remove approximately 400 to 500 mL weekly or fortnightly during induction, individualising volume and interval for body size, symptoms, haemoglobin and tolerance.
2Check haemoglobin before each session, reduce frequency if below 120 g/L and pause if below 110 g/L while evaluating the cause; measure ferritin frequently as the target approaches.
3Aim for ferritin about 50 micrograms/L but not lower in induction, then maintain 50 to 100 micrograms/L with an interval often between monthly and four-monthly.
4Second lineIf venesection is infeasible, refer for specialist erythrocytapheresis or second-line iron chelation rather than improvising an unmonitored substitute.

04Joint symptom pathwayTreat OA and CPP disease in parallelPain or function persists irrespective of ferritin response.

1Classify chronic mechanical pain, active synovitis and acute hot-joint flares; aspirate an acute effusion when infection or another crystal remains possible.
2Use tailored education, strengthening, range and aerobic activity, weight support where relevant and topical NSAID before systemic analgesia when suitable.
3Consider image-guided intra-articular steroid after infection exclusion or orthopaedic referral for severe structural disease; explain that venesection may not reverse joint damage.

05Family and prevention pathwayReduce avoidable future harmA pathogenic HFE phenotype is confirmed.

1Offer adult first-degree relatives counselling and appropriate targeted testing, explaining incomplete penetrance and the distinction between genotype and clinical disease.
2Avoid iron supplements unless a separate deficiency is proven, avoid high-dose vitamin C supplements, moderate alcohol especially with liver injury and avoid raw shellfish because iron overload increases severe Vibrio risk.
3Do not prescribe an extreme low-iron diet as a substitute for venesection; support vaccination, metabolic risk reduction and ordinary balanced nutrition.

Key medicines and prescribing safety3 treatments · regimens, roles and cautions

First-line disease-modifying treatment for confirmed iron overload in a suitable non-anaemic person; it prevents systemic iron injury but is not a reliable treatment for established arthropathy.

Therapeutic venesection

In induction, remove about 400 to 500 mL of blood weekly or every two weeks, individualised to size and tolerance, until ferritin is about 50 micrograms/L but not lower. In maintenance, repeat often every 1 to 4 months to keep ferritin around 50 to 100 micrograms/L.

This is a supervised procedure, not a self-directed blood-donation schedule. Check haemoglobin before every session, reduce frequency below 120 g/L and pause below 110 g/L under the treating pathway. Adjust for frailty, low body mass, hypotension or cardiac disease. Venesection is commonly paused or reduced during pregnancy unless specialist benefit outweighs maternal-fetal risk.

First-line medicine for local osteoarthritis-like joint pain when an NSAID is appropriate, alongside exercise and function support.

Diclofenac 1.16% gel

Apply 2 to 4 g over the painful hand or other superficial joint three or four times daily for the shortest useful period; wash the hands afterwards unless they are the treatment site.

Avoid broken skin, NSAID allergy and unreviewed concurrent NSAIDs. Systemic renal, gastrointestinal and cardiovascular harm remains possible with high-area or prolonged use. Avoid in the third pregnancy trimester and obtain medicine-specific advice earlier in pregnancy or during breastfeeding.

Short-term adjunct for one persistently inflamed osteoarthritic or CPP-associated joint when pain obstructs rehabilitation; it does not alter systemic iron or established structural disease.

Intra-articular triamcinolone acetonide

After aspiration and infection exclusion, inject 5 to 10 mg into a small joint or up to 40 mg into a large joint using the 40 mg/mL suspension; select the lowest dose for joint size and inflammation and use strict asepsis.

Haemochromatosis arthropathy is not a named licensed indication. Never inject a possibly septic joint or tendon. Warn about infection, post-injection flare, skin or fat atrophy and transient hyperglycaemia; diabetes, anticoagulation, pregnancy and repeated requests require individual specialist review.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Progressive arthropathy

Persistent hand, wrist, ankle, hip or knee pain, stiffness and structural loss can impair grip, mobility and employment even when systemic iron is adequately controlled.

Acute CPP crystal arthritis

Associated chondrocalcinosis can produce abrupt inflammatory attacks that resemble gout or infection and may recur independently of ferritin concentration.

Cirrhosis and liver cancer

Untreated hepatic iron loading causes fibrosis and cirrhosis; established advanced fibrosis retains hepatocellular-carcinoma risk after successful iron depletion.

Endocrine and cardiac disease

Diabetes, hypogonadotropic hypogonadism, osteoporosis, cardiomyopathy and arrhythmia are major preventable causes of morbidity when diagnosis is delayed.

Treatment-related anaemia

Over-frequent venesection can cause low haemoglobin, fatigue, presyncope and poor adherence; a falling haemoglobin requires interval adjustment and reassessment for another cause.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Before each induction venesection, record haemoglobin, symptoms, pulse and blood pressure and reassess volume or interval after presyncope, disproportionate fatigue or poor recovery.
Measure ferritin about monthly or every four venesections during early induction and more frequently as it approaches 200 micrograms/L and the 50 micrograms/L target.
During maintenance, check ferritin and haemoglobin at least every six months or more often while the interval is being established, avoiding both reaccumulation and iron-deficiency anaemia.
Track liver enzymes, fibrosis status, glucose, cardiac and endocrine symptoms according to baseline organ involvement; normal ferritin does not remove established cirrhosis surveillance.
Record joint-specific pain, morning stiffness, grip, walking, attacks and activity separately from ferritin so persistent structural disease receives appropriate care.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

The knuckles are a systemic clue

MCP2 and MCP3 degeneration is unusual for primary hand osteoarthritis and should prompt iron studies, particularly with hook osteophytes or chondrocalcinosis.

Ferritin is not a standalone diagnosis

Inflammation, metabolic dysfunction, alcohol and liver injury raise ferritin; transferrin saturation, genotype and sometimes hepatic MRI establish iron loading.

Genotype is not destiny

Many C282Y homozygotes never develop organ damage, while a single HFE variant rarely explains major overload without another cause; phenotype determines treatment.

Iron control and joint control diverge

Biochemical iron depletion can be excellent while pain persists because cartilage loss, osteophytes and CPP deposits are not reliably reversible.

11Common pitfallsFrequent interpretation and management errors.

01
Diagnosing hereditary haemochromatosis from an isolated high ferritin without transferrin saturation, inflammation and liver context.
02
Attributing major iron overload to C282Y carrier or H63D status without phenotypic confirmation and exclusion of secondary causes.
03
Missing the diagnostic significance of second and third MCP disease, radial hook osteophytes or early widespread CPPD.
04
Promising that venesection will reverse established joint pain and stopping joint-specific rehabilitation when ferritin normalises.