Best Practice & Research Clinical Rheumatology 25 (2011) 649–664

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Best Practice & Research ClinicalRheumatology

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3

Haemochromatosis: The bone and the joint

Pascal Guggenbuhl, MD, PhD, Professor of Rheumatology a,b,c,*,Pierre Brissot, MD, PhD, Professor of Hepatology c,d,e,Olivier Loréal, MD, PhD, Research Director a,c,e

a INSERM UMR 991, F-35000 Rennes, Franceb Service de Rhumatologie, Hôpital Sud, CHU F- 35000 Rennes, FrancecUniversité de Rennes 1, IFR 140, F- 35000 Rennes, Franced Service des Maladies du Foie, INSERM UMR 991, F-35000 Rennes, FranceeCentre de Référence des Surcharges en Fer rares d’Origine Génétique, Hôpital Pontchaillou, F-35000 Rennes, France

Keywords:HaemochromatosisIronHFE geneHepcidinOsteoporosisChondrocalcinosisOsteoarthritisCPPDOsteoporosisFracture

* Corresponding author. INSERM UMR 991, F-35E-mail addresses: Pascal.guggenbuhl@chu-ren

loreal@univ-rennes1.fr (O. Loréal).

1521-6942/$ – see front matter � 2011 Publisheddoi:10.1016/j.berh.2011.10.014

Genetic haemochromatosis is a hereditary disease characterised bytissue iron overload. In Caucasians it is most often due to homo-zygous C282Y HFE gene mutation, but other genes may beinvolved. Without treatment by venesections, patients can developlife-threatening visceral damage such as liver cirrhosis and carci-noma, diabetes or heart failure. This treatment has been remark-ably successful in preventing these complications, but patientssurvive with other symptoms of the disease susceptible to impair,sometimes seriously, their quality of life. This is the case ofarthropathy and osteoporosis complicating haemochromatosis. Inthis chapter, focus has been placed on the rheumatologicalcomplications of genetic haemochromatosis.

� 2011 Published by Elsevier Ltd.

Genetic haemochromatosis (GH) is a hereditary disease expressed by tissue iron overload. It is dueto an intestinal hyperabsorption of iron. The most common genotype is homozygosity for thep.Cys282Tyr mutation of the HFE gene (MIM 235200). However, other genetic conditions have beendescribed. The central role of hepcidin is now recognised. Before phlebotomy therapy, GHwas a seriousdisease which could lead to vital complications such as cirrhosis, liver carcinoma, heart failure ordiabetes mellitus because of iron overload. Currently, these complications can be prevented by regular

000 Rennes, France.nes.fr (P. Guggenbuhl), Pierre.brissot@univ-rennes1.fr (P. Brissot), Olivier.

by Elsevier Ltd.

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blood removal. However, despite treatment by phlebotomies, patients’ quality of life is often altered bythe rheumatological conditions of the disease, particularly joint symptoms and sometimes osteopo-rosis. That is why rheumatologists are in first line to diagnose the disease and to treat bone and jointdamage.

Genetics and physiopathology

GH was originally reported by Trousseau in 1865 [1]. The major finding was the presence of a triadassociating cirrhosis and diabetes in a tanned man. The picture of the disease has been progressivelycompleted until now. Von Recklinghausen reported, in 1889 [2], the presence of strong iron depositswithin the liver of those patients, thus leading him to evoke the role of iron excess in the diseaseoccurrence. He named the disease haemochromatosis. Thereafter, a large contradictory debate wasinitiated to identify the etiology of this ‘idiopathic’ iron overload occurring out of haematologicaldisease and iron supplementation. Some people supported the role of associated factors, such asalcohol, in its development, leading to the hypothesis of secondary iron overload linked to excessivealcohol intake. However, others supported the hypothesis of a primary iron overload disease linked togenetic factors [3,4]. Simon et al. definitively demonstrated in 1976 that the original clinical picturewasrelated to genetic factors, linking the disease to chromosome 6, more specifically in area p21, close toHLA genes which were subsequently used for family studies for 20 years [5]. In addition, he demon-strated that the transmission of this GH was recessive. At the same time, the clinical description of GHwas completed especially with the reports of patients exhibiting cardiac complications, osteoporosisand arthritis, hypogonadism and dermoskeleton alteration [6].

Understanding of the pathophysiology of the development of iron overload and its complications isa major challenge to improve the follow-up of haemochromatosis patients as well as to increase, fromthis ‘model disease’, our knowledge of iron metabolism.

Normal iron metabolism

Iron, a transition metal, is required for cell life. It is involved in a large number of biological func-tions, especially in oxygen transport when associated with haemoglobin, and also in the activity ofa large number of enzymes, requiring iron as a cofactor and playing a role in the different metabolisms.For this purpose, iron must be present in sufficient concentrations and adequately distributed to thedifferent cell types requiring the presence of iron [7].

The total amount of iron in the body is close to 4 g for an adult. Such a quantity of iron must bestrictly controlled to ensure that the amount of iron is sufficient, to avoid manifestations linked to irondeficiency, and not excessive to limit its potential toxicity. The control of iron stores and distributioninvolves a large number of genes encoding proteins, thus ensuring iron metabolism homeostasis.Mutations in some of these genes may promote the development of genetic iron overload [8]. We willbriefly describe iron metabolism before the presentation of GH pathophysiology.

Plasma plays a major role in iron metabolism. Indeed, despite the fact that plasma iron concen-tration is low (12–25 mM), this iron form is the only one available for cells. Therefore, the control ofplasma iron is a major goal. The main sources of iron for plasma are macrophages and enterocytes. Thecontrol of iron import in plasma from these cells involves hepcidin.

Macrophages are involved in recycling iron from erythrocytes [7]. Indeed, erythrocytes concentrate70% of the body iron for incorporation into haemoglobin. When erythrocytes reach their lifespan, theyundergo the erythrophagocytic process within macrophages. Haem is then extracted from erythro-cytes and iron is released under the haem oxygenase action. Iron can therefore be stored in macro-phages within ferritin – the iron-storage protein which may contain up to 4500 iron atoms undera chemically inactive form – or released in plasma through the ferroportin protein. Ferroportin isa protein encoded by the SLC40A1 gene and located in the cell membrane [9,10]. It transfers ferrousatoms of iron (Fe2þ) from the macrophage cytoplasm towards plasma. In addition, iron must beoxidized to Fe3þ (the ferric form of iron) to be taken in charge by transferrin, the plasma iron transportprotein. Eachmolecule of transferrin may link two atoms of iron. Ceruloplasmin, a multicopper oxidasesynthesised by the liver, ensures this oxidase activity [11]. A transferrin saturation coefficient,

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corresponding to the ratio of plasma iron concentration versus total plasma transferrin concentration,can be calculated (normal range values 30–45%). The quantity of iron released daily by macrophages isclose to 20 mg and ensures the maintenance of the plasma iron level throughout the day.

Enterocytes also play a role in themaintenance of iron concentration in plasma and therefore of ironstores. Indeed, every day, there are nonregulated and incompressible losses of iron, especially throughcell desquamation, urine, feces and menses in women [7]. Therefore, iron must be extracted fromnutrients and absorbed to compensate for its losses. In addition, pregnancy and growth phases requiremore iron. Iron absorption takes place in the duodenum at the apical pole of enterocytes, throughmechanisms involving specific transporters [12]. Iron is then either addressed to ferritin and storedwithin the enterocyte, or directed towards the basolateral pole of the enterocyte. When stored in theenterocyte, iron is not absorbed due to enterocyte desquamation into digestive lumen. Whenaddressed to basolateral pole of enterocyte, atoms of iron are in a position to be released in plasma,through the ferroportin protein [9,10]. Like in macrophages, an oxidation phase occurs thereafter toensure the association of iron to transferrin. This is performed by hephastin, a glyco-sylphosphatidylinositol (GPI) -anchored protein with ferroxidase activity [13].

Hepcidin is a peptide of 25 amino acids in its mature form, synthesised by hepatocytes and secretedin plasma [14–17]. It targets the ferroportin protein which is especially located in macrophages andenterocytes. When interacting with ferroportin, hepcidin promotes its internalisation and then itsdegradation through the proteasome. Therefore, the hepcidin level, by limiting ferroportin expressionat the cell membrane, controls the iron leakage into plasma and modulates both plasma iron andtransferrin saturation levels. The plasma hepcidin level is regulated by various stimuli. Thus, secondaryiron excess induces hepcidin expression through a molecular cascade involving the Bone Morphoge-netic Protein 6 (BMP6) produced by iron-loaded hepatocytes and interacting at the cell membranewitha complex associating a specific BMP receptor [18,19], composed of two subunits, and haemojuvelin asa co-receptor. Then, phosphorylated BMP receptors induce a phosphorylation of cytoplasmic SMAD1/5/8 proteins which then interact with SMAD4. The SMAD1/5/8/4 complex is translocated to thenucleus and interacts with a specific BMP-responsive element in the hepcidin promoter, thus inducingtranscription of the hepcidin mRNA [20]. The increase of plasma hepcidin concentration limits ferro-portin expression at the cell membrane and therefore decreases the plasma iron levels to counteractthe iron excess.

Other genes also play a role in the signal transduction related to iron: the HFE gene product isexpressed at the cell membrane in association with the beta2 microglobulin and favours the signallinked to BMP6 [21]; the gene TFR2, coding the transferrin receptor 2, also plays a role in the iron-related regulation of hepcidin expression [22]. Despite the demonstration of the positive role ofthese two genes in the control of hepcidin expression, precise mechanisms are not fully characterised.Inflammation also strongly promotes hepcidin expression, especially due to the increase ofinterleukin-6 levels which stimulate, through the cell receptor, the STAT3 pathway and therefore thetranscription of the hepcidin gene, thanks to a specific binding site for phosphorylated form of STAT3in the hepcidin promoter [23–25]. During inflammation, such abnormally high hepcidin levelsregarding the iron stores promote iron retention in macrophages and limit iron absorption. This playsa role in the development of anaemia related to chronic diseases. Conversely, hepcidin levels aredecreased by hypoxia and anaemia. Mechanisms could involve i) the hypoxia transcription factorhypoxia-inducible transcription factor (HIF) [26] and ii) a soluble signal linked to the increase oferythropoietic activity required to compensate hypoxia. The role of growth developmental factor 15(GDF15) has been evoked [27].

Pathophysiology of iron overload in GH

The original description of GH corresponds to the disease related to the homozygous p.Cys282Tyrmutation in HFE gene which represents more than 95% of GH. However, other causes of GH have beendescribed more recently. Most of the cases of GH are related to an inappropriately low hepcidin levelleading to increased iron leakage frommacrophages and enterocytes and then to an increase of plasmairon and transferrin saturation. Other types of GHs are linked to ferroportin gene mutations.

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Hepcidin deficiencyHepcidin deficiency has been described in haemochromatosis linked to mutations in hepcidin,

haemojuvelin, HFE or transferrin receptor 2 genes [28,29]. This leads to a plasma iron increasefavouring the appearance of non-transferrin-bound iron (NTBI) which plays an important role in thedevelopment of iron overload [30].

Genes involved in hepcidin deficiency. It is obvious that homozygous or compound heterozygote muta-tions in the coding sequence of the hepcidin gene itself strongly inhibit hepcidin expression, thereforeleading to extremely severe GH with juvenile expression. Fortunately, such mutations are exceptional[31]. It is noteworthy that somemutations in the 50-untranslated region of themRNA or in the hepcidinpromoter may have an impact on hepcidin expression [32,33].

Mutations (homozygous or compound heterozygote) in the haemojuvelin gene are very rare andalso induce a juvenile form of GH [34]. This impact is related to the major role of haemojuvelin proteinin the transduction of BMP6-related signaling in hepcidin expression regulation [35].

The homozygous p.Cys282Tyr (C282Y) mutations of the HFE gene also favor the development ofa situation of abnormally low hepcidin levels, leading to the development of iron overload [36]. Thismutation is found at the heterozygous state in 10% of the Caucasian population, and 3 per 1000 arehomozygous and therefore exposed to the risk of iron overload development. The mutation alters thesignal transduction linked to BMP6 [21]. However, the penetrance of the disease is quite variable[29,37], ranging from an absence of bioclinical expression to severe organ damage compromising lifeexpectancy. This suggests that other environmental or genetic factors could play a role in the pene-trance of the disease. It is noteworthy that the p.His63Asp (H63D) polymorphism alone, present in 30%of Caucasians, does not induce the development of iron overload. Other rare deleterious mutations ordeletions have been reported [38,39].

Homozygous or compound heterozygous mutations in the TFR2 gene also induce low levels ofhepcidin by mechanisms not yet fully understood. It is noteworthy that some cases of the disease havebeen recorded in younger patients compared to HFE-related haemochromatosis [40].

Role of NTBI in the development of iron overload. When transferrin saturation increases, NTBI may appearin plasma [30,41,42]. In normal situations, plasma iron is linked to transferrin, a protein secreted byhepatocytes, which ensures iron delivery to cells. Mechanisms of uptake implicate transferrin receptor1, a cell membrane protein linking transferrin and allowing its endocytosis. This mechanism iscontrolled by the iron regulatory protein (IRP)/iron-responsive element (IRE) couple. In a condition ofcell iron excess, the cytoplasmic IRPs do not further interact with the IREs which are nucleotidicsequences localised in the 30-untranslated region of the transferrin mRNA. This allows degradation oftransferrin mRNA and then limits transferrin iron uptake in condition of cellular iron excess [43]. NTBIuptake is not downregulated in such situations [44,45]. Therefore, iron continues to enter the celldespite iron overload. NTBI being especially uptaken by liver, pancreas and heart, this explains why itplays a key role in the development of iron overload.

Ferroportin diseaseFerroportin is the target of hepcidin, and mutations in the SLC40A1 gene also induce GH [46]. It is

noteworthy that the transmission of the disease is dominant. The mutation may have two differentimpacts which correspond to a loss or a gain of function.

Loss of function is the most frequent consequence of the mutation [47,39]. In this case, the mutationlimits either the expression of the protein at the cell membrane or its capacity to export iron to plasma.Therefore, iron egress is limited especially frommacrophages which are overloaded. This explains thatthe phenotype of the disease is characterised by plasma iron and transferrin saturation which areeither normal or decreased. Hepatocytesmay also present some degree of iron overloadwhich could berelated to the fact that some of them express low levels of ferroportin [48] or to another unknownmechanism, NTBI being undetectable in those patients. In addition, despite the decrease of ferroportinfunction, digestive iron absorption is not abolished, suggesting that other mechanisms involved in ironuptake may exist.

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Gain of function applies to a few cases. The ferroportin gene mutation leads to structural changeswith impossibility for hepcidin to interact with ferroportin which keeps its iron export capacity. Then,the disease is characterised by a phenotypic presentation similar to hepcidin deficiency with increaseof plasma iron and transferrin saturation.

Diagnosis and phenotypic classification

Iron overload is suspected in two situations: in the presence of clinical symptoms (knowing thatmany of them are non-specific), and, most often, when plasma transferrin saturation is increased (intheory >45%, but in practice often >60% in men and >50% in women) or plasma ferritin is >300 mg l–1

in men and >200 mg l–1 in women.Clinical symptoms suggestive of GH are: chronic asthenia, arthralgia, arthritis, chondrocalcinosis,

skin pigmentation, hepatomegaly, unexplained liver disease, type 1 diabetes, osteopenia or osteopo-rosis, and cardiac symptoms (rhythm disturbances, cardiac failure).

For HFE-related haemochromatosis (type 1 haemochromatosis), the diagnosis is based on theassociation of increased transferrin saturation (TS) and the p.Cys282Tyrmutation in a homozygous state.

However, clinicians have to diagnose non-HFE haemochromatosis and rule out hyperferritinemianot related to haemochromatosis by checking for the main causes of non-haemochromatosis ferritinincrease such as alcohol, inflammation, cell necrosis or dysmetabolic iron overload syndrome. Adecision tree is proposed in Fig. 1 adapted from [49], based on suggestive symptoms and signs and/orhyperferritinemia.

Briefly, if TS is >45%, HFE testing is performed to find C282Y homozygous patients or, more rarely,compound heterozygote patients C282Y/H63D who have a much lower chance of developing iron

HyperferritinemiaLook for

Suggestive symptoms of hemochromatosis

- Alcohol abuse- Inflammation- Cell necrosis

Metabolicsyndrome- Metabolicsyndrome

TSTS > 45% TS < 45%No hemochromatosis

Liver MRI or biopsy

HFE

HIC normal HIC

C282YHomozygosity

No C282Y Homozygosity

ExcludeAlcoho

ExcludeAlcoho inflammationE l d

T 1Non HFE

Alcohol,dysmetabolic

syndrome

Alcohol, inflammation,cell necrosis,

dysmetabolic syndrome

ExcludeCirrhosis or

myelodysplasia

Type1Haemochromatosis

Haemochromatosis(Type 2, 3 or 4B) - Ferroportin disease (4A)

- Aceruloplasminemia- L-Ferritin- ±cataract

Fig. 1. Algorithm for the diagnosis of genetic causes of hyperferritinemia (adapted from [49]). TS: transferrin saturation; HIC: hepaticiron concentration.

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overload in the absence of other environmental factors. When no mutations for HFE are found, non-HFE haemochromatosis is to be considered (type 2, 3 and 4B).

If TS is<45% and hyperferritinemia not related to haemochromatosis is ruled out, liver iron contenthas to be evaluated by magnetic resonance imaging (MRI) or biopsy. In the case of hepatic ironconcentration (HIC) increase, ferroportin disease or hereditary aceruloplasminemia can be considered;if HIC is normal, the hyperferritin-cataract syndrome has to be investigated.

A phenotypic five-scale grading has been proposed [50] to summarise the impact of the disease(Fig. 2) and to make a decision for treatment. Stage 0: genetic predisposition (genotype) without anyclinical phenotype; stage 1: stage 0þ isolated increased transferrin saturation (>45%); stage 2: increasein both transferrin saturation and serum ferritin (>200 mg l–1 inwomen and>300 mg l–1 inmen): this isthe cut-off for treatment; stage 3: decrease of quality of life due to asthenia and/or arthropathy; andstage 4: life-threatening symptoms such as liver cirrhosis, diabetes, cardiomyopathy and hepatocellularcarcinoma.

The FrenchNationalHealthAuthorities (HauteAutorité de Santé (HAS)) published recommendations(with an English version) for assessment of patients with type 1 haemochromatosis according to thephenotypic scale (http://www.has-sante.fr/portail/upload/docs/application/pdf/hemochromatosis_guidelines_2006_09_12__9_10_9_659.pdf).

Stage 0 and 1. No tests are required, but a careful physical examination looking for asthenia, mel-anodermia, arthralgia and familial haemochromatosis is necessary. Ferritin and TS should be assessedevery 3–5 years or in the case of new clinical signs.

Stages 2, 3 and 4. In addition to serum iron overload assessment and physical examination, fourorgans are targeted:

- Liver: Transaminases, liver ultrasound in the case of clinical hepatomegaly or transaminaseincrease. In the case of transaminase increase, hepatomegaly or ferritin above 1000 mg l�1 a liver

↑ TS

↑ SF

↑ TS0

(100%)

1

(75%)

2

(50%)

3

(25%)

4

(< 10%)

↓ Quality

of life

↑ TS

Life-threateningcomplications**

↓ Quality

of life*

↑ TS

↑ SF ↑ SF

Genetic susceptibility Biochemical expression Clinical expression

Fig. 2. Haemochromatosis phenotypic grading scale for severity of the disease (adapted from [50]). TS: Transferrin Saturation; SF:Serum Ferritin. *fatigue, arthropathy, **cirrhosis, hepatocellular carcinoma, diabetes, heart failure.

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biopsy is indicated. This is not for the diagnosis of haemochromatosis which is made on bothserum iron parameters and genotyping, but to detect liver fibrosis and especially cirrhosis.

- Gonads: Hypogonadism is assessed in males, clinically and biologically with testosterone dosage.- Bone: DualX-rayabsorptiometry (DXA) is indicated todiagnoseosteopeniaorosteoporosis in thecaseof osteoporosis cofactors such as hypogonadism in males and osteoporosis in females or cirrhosis.

- Heart: An echocardiography is required.

Different types of hereditary haemochromatosis

Type 1 haemochromatosis [29]

This is by far the most frequent form of haemochromatosis. It concerns Caucasians and especiallyCeltic populations. It is due to the p.Cys282Tyr (C282Y) mutation of the HFE gene, located on chro-mosome 6. Homozygosity is the condition for developing the disease, even if the clinical penetrance isfar from being 100%. Compound heterozygosity C282Y/H63D does not lead to clinical iron overload[34]. One woman in one hundred and 25% of menwith C282Y homozygosity have a phenotype of ironoverload [51]. This means that other genetic and environmental factors are needed to develop thedisease and are susceptible to modify the disease expression. Combinations withmutations inHAMP orHJV genes are rare. BMP2 variants have been found to increase the penetrance of C282Y homozygosity.However, these situations are rare [39]. Alcohol abuse, transfusions, dysmetabolic hepatosiderosis orchronic iron supplementation may represent environmental factors.

Type 2 haemochromatosis [31,34]

It is also known as ‘juvenile hemochromatosis’. Mutations on two different genes can be involved.The type 2A hemochromatosis is related to mutations in the hemojuvelin gene (HJV) located onchromosome 1. Type 2B hemochromatosis is characterised by hepcidin gene (HAMP) mutations. Thisleads to an early and massive iron overload with predominant heart and endocrine damages. Fortu-nately, this type remains exceptional.

Type 3 haemochromatosis [52]

It is a rare form of hemochromatosis related to mutations of transferrin receptor 2 (TFR2). Pheno-typic expression resembles that of type 1 hemochromatosis.

Type 4 haemochromatosis [46]

It is more frequent than type 2 and 3 hemochromatosis. It is also called ‘ferroportin disease’ and isrelated to mutations in the ferroportin gene (SCL40A1) on chromosome 2. It is the only type ofhemochromatosis transmitted in an autosomal dominant way. The 4 A type is due to mutations onthe SCL40A1 gene resulting in a loss of function and haemochromatosis with iron overload in thereticuloendothelial system: spleen macrophages and Kupffer cells with normal or low plasma ironand transferrin saturation. The 4 B type makes the ferroportin resistant to hepcidin which results ina gain of function leading to a permanent release of iron in the plasma. Recent data suggesta preeminent role of sex and environmental or acquired factors in the phenotypic expression of thedisease [53].

Joint symptoms in hemochromatosis

Joint pain is very frequent in hemochromatosis. Two-thirds of patients complain of joint symptomswhich represent a major cause of impaired quality of life; in one-third of cases hemochromatosis isrevealed by articular pain [51,54]. Diagnosis could be difficult when the context of iron overload is not

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known. Indeed, because rheumatological symptoms are not clinically specific to haemochromatosis,the picture can mimic some frequent pathologies such as osteoarthritis, chondrocalcinosis or calciumpyrophosphate deposition (CPPD) disease. It can result in monoarthritis or polyarthritis and the axialskeleton can be involved. Pain crisis can have a degenerative or inflammatory profile. In some cases,joint deformities may direct the physician firstly to a rheumatoid arthritis diagnosis. For physicians, itis important to pick up some peculiarities of haemochromatosis arthritis, both clinically andradiologically.

Clinical presentation of hemochromatosis arthritis

Haemochromatosis arthritis is very similar to CPPD and osteoarthritis. Therefore, it is important todetermine when it must be considered.

Firstly and very importantly, patients are younger than in the primitive forms of both diseases.Symptoms can begin before 30 years of age in men (or even earlier in the juvenile forms unrelated toHFE), but usually after the menopause in women. In a recent series of 199 patients, the average age ofpatients with their first joint symptoms was 45.8 � 13.2 years, with a delayed diagnosis of 9 � 10.7years [55]. Some locations are very classic, such as the second and third metacarpophalangeal (MCP)joints causing the classic sign of ‘pain at the handshake’. The symptoms usually differ from those ofinflammatory arthritis affecting the MCP joints and particularly rheumatoid arthritis. There is usuallyneither pain at night nor extended morning stiffness. Pain is linked to motion with stiffness limitingflexion, and a gradual onset of slightly inflammatory swelling. The wrists are often affected as well asproximal interphalangeal joints. Involvement of the hips, knees and ankles is common. Less frequently,the shoulders, elbows and spine are concerned [56,57].

Joint involvement in haemochromatosis is far from being minor. Several studies report a highnumber of prosthetic replacement joints compared to the general population. In one study, the risk wasmultiplied by 9 (confidence interval ¼ 4.6–17.4, p ¼ 8.71 � 10�11) in patients with haemochromatosis(n ¼ 199) compared to a control cohort of patients adjusted for age, sex, menopause, diabetes, C-reactive protein or body mass index and free of haemochromatosis (n ¼ 824). A prosthesis had beenfitted in 16.1% of patients with haemochromatosis at a mean age of 58.3 � 10.4 years, with 43.8% ofthem having two prostheses and 9.4% three. The most common location was by far the hip (84.6%)followed by the knee (11.5%) and ankle (3.8%). Prosthetic replacement was earlier in the case ofhemochromatosis among subjects operated on: 21.9% versus 1.7% before the age of 50 years(p ¼ 0.0027) and 50% versus 8.6% before the age of 60 years (p ¼ 8.9 � 10�6) [58]. This finding wasconfirmed in a case–control study conducted by self-administered questionnaire from haemochro-matosis patients belonging to an association of patients (n ¼ 306) and controls (n ¼ 304). Afteradjusting for age, sex and body mass index, patients reported more hip (11.1% vs. 2.3%; odds ratio ¼ 5.2(2.2–11.9), p¼ 0.0001) and knee replacements (3.3% vs. 0.7%; odds ratio¼ 5.3 (1.1–25.6), p¼ 0.03) thanin the control population [59].

Radiological presentation of haemochromatosis arthritis

Radiological semiology of hemochromatosis arthritis is close to CPPD. Very recently, the EuropeanLeague against Rheumatism (EULAR) established guidelines on CPPD. haemochromatosis was clearlyidentified as a cause of this affection. It was stated that haemochromatosis had to be assessed in thecase of CPPD or chondrocalcinosis [60].

The most characteristic sign of haemochromatosis arthritis is the specific location on the MCP joints2 and 3. The hook-shaped osteophyte of the metacarpal head is a very characteristic sign of haemo-chromatosis (Fig. 3); very often, there is a joint space narrowing of the MCP joint associated. Wrist anddistal radioulnar joints are frequently affected, whereas similarly to MCP joints, these joints are usuallyunaffected in primary osteoarthritis. Isolated narrowing of the scaphoidtrapezium joint, withoutthumb osteoarthritis, is also suggestive of CPPD or haemochromatosis. Sometimes, chondrocalcinosiscan be observed. Subchondral sclerosis with cysts in the chaplet is also suggestive of the diagnosis(Fig. 4). In some cases, it is not possible to differentiate between osteoarthritis and haemochromatosisarthropathy. Some locations are suggestive of haemochromatosis, especially for MCP joints, wrists,

Fig. 3. Haemochromatosis arthritis of 2nd and 3rd MCP with hook-shaped osteophyte of the 3rd metacarpal head.

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elbows, ankles or shoulders (centred glenohumeral osteoarthritis) (Fig. 5). Sometimes, haemochro-matosis leads to erosive arthritis which can mimic rheumatoid arthritis.

Recently, a radiographic score has been proposed to standardise studies. Radiographs of the hands,knees and ankles were scored for joint space narrowing, erosions, osteophytes and chondrocalcinosis.Moreover, the severity of the arthropathy was graded from 0 to 3. This is clearly a step forward forfurther studies of haemochromatosis arthritis. However, there are some problems of reproducibility forsome items and some joints [61].

Haemochromatosis arthritis pathophysiology

The question raised is as follows: is there a direct role of iron in the genesis of arthropathy inhaemochromatosis?

The link has never been clearly established; however, many arguments go in this direction. Clinicalstudies suggest a link between iron overload and joint damage. Ferritin levels in serum have beenfound correlated to the number and the severity of subchondral arthropathy [54]. In another study,there was an increase of joint disease in a group of patients with ‘probable or definite’ haemochro-matosis versus patients with ‘possible or probable’ disease. There was a correlation between a serumferritin level >1000 mg l–1 and the rheumatological condition [62]. A previous series found a linkbetween MCP arthropathy and the degree of iron overload [63].

Considering this hypothesis, it is surprising that phlebotomies, in contrast with the visceral loca-tions of the disease, in many cases do not have any favourable impact on this rheumatism [64]. In thearticle by from Sahingegovic et al., only 13.6% of the patients had an improvement of their jointsymptoms after desaturation [55]. A small series of 18 patients showed that patients with phleboto-mies had a paradoxical increase of CTXII, a marker of cartilage degradation, suggesting an impact ofiron removal on cartilage metabolism [65]. The only study which reported an improvement of jointpain of 46% in 62% of patients with haemochromatosis after venesections was a retrospective surveywithout direct physical examination [66].

In osteoarthritis, ferritin levels in synovial fluidwere increased in patients with heterozygous C282Yor H63D mutation compared to patients without this mutation even though serum ferritin levels weresimilar in the two groups. Synovial iron sequestration was suggested to explain the lack of

Fig. 4. Subchondral sclerosis with cysts in chaplet in the ankle in haemochromatosis.

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improvement of joint symptoms with iron removal. However, it is not known if the same results areobtained with homozygous C282Y patients [67].

The synovial histology is similar to that in osteoarthritis [68] with more macrophages andneutrophil granulocytes, as it is found in rheumatoid arthritis, especially in patients with majordeposits of hemosiderin [69]. It could be speculated that iron, found in chondrocytes, stimulatescartilage catabolic enzymes leading to joint impairment. Patients with juvenile haemochromatosis andmassive iron overload have haemochromatosis arthritis; this supports the role of iron in thearthropathy pathogenesis [57].

Other hypotheses have been considered: inhibition of pyrophosphatases by iron leading tochondrocalcinosis; a PTH 44–68 fragment increase; or an association between genotype and IL1RNlevels in patients with haemochromatosis and joint pain [54,56,70,71]. The HFE protein is similarto that of other major histocompatibility complex class-1 proteins; C282Y HFE mutation is asso-ciated with abnormal expression of MHC class I molecules and an impaired class I antigenpresentation pathway [72].

Fig. 5. Centered glenohumeral osteoarthritis in haemochromatosis.

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Bone loss in GH

Clinical aspects of osteoporosis in haemochromatosis

Bone involvement in GH is classical [73]. It was first described in 1960 in France by Delbarre et al.[74] Unfortunately, it was initially attributed to alcoholism or hypogonadism, two conditions leading toosteoporosis and frequently associated with haemochromatosis. However, these assumptions are nolonger valid. Currently, diagnosis of haemochromatosis is made very early, very often at stage 2 of thedisease, without visceral complications, and nevertheless osteoporosis is not rare, even thoughhypogonadism itself has become rare: 6% in males and 5% in females [75]. Moreover, the genotype canrule out the sole responsibility of putative alcoholism in bone loss. In recent series with hemochro-matosis genotyping and bone assessment with DXA (dual X-ray absorptiometry), which is the standardtechnique for osteoporosis assessment, the prevalence of osteoporosis (T score < �2.5) was comprisedbetween 25.3% and 34.2% [76–78]. Fracture frequency is less well known. It has been estimated at 20%of patients in an old study, before the HFE genewas discovered [79]. There are no series collecting dataon systematically peripheral fractures and vertebral fractures which require, for the latter, systematicspine X-rays. Indeed, two-thirds of osteoporotic vertebral fractures have few or no clinical symptoms tothe extent that patients do not consult their doctor. However, fractures are sometimes the way todiagnose haemochromatosis [80,81]. Osteoporosis has been described in juvenile haemochromatosis[82]. Despite this, apart from in France (see Diagnosis and Phenotypic Classification), internationalguidelines for haemochromatosis do not include osteoporosis assessment [49,83].

Pathophysiology of bone loss in haemochromatosis

More recent studies in this field show that osteoporosis associated with haemochromatosis is notdue to hyperparathyroidism, vitamin D deficiency, hypogonadism or liver failure even if they can beresponsible for secondary osteoporosis [54,76–78]. Therefore, it is possible that iron has a directtoxicity on bone metabolism [84]. Human studies have shown a negative correlation between HIC andbone mineral density (BMD) at the femoral neck, and between serum ferritin or the quantity ofremoved iron and lumbar BMD. Changes in bone turnover markers are not very informative [77,78].There are few data on human bone biopsies. Usually, they come from old studies and are biasedbecause of the lack of genotype, the presence of hypogonadism, cirrhosis or alcoholism. They showedan increase in bone resorption area and a decrease in osteoid thickness, which means an increase inosteoclasts (bone resorption) and a decrease in osteoblast (bone formation) activity [85,86].

In minipigs with exogenous iron overload, there was a decrease in bone formation without anychange in bone resorption [87]. In vitromodels showed the samedecrease in osteoblast function [88,89].Conversely, other models showed a global increase in bone remodeling in rats [90]. In HFE knockoutmice, there was a phenotype of bone loss, with iron found in bone trabeculae with Perl’s staining, anda significant increase in osteoclasts and not in osteoblast number [91]. In vitro, iron is capable ofinhibiting bone crystal growthwith significant changes in crystallinity and carbonate substitution [92].

Management of haemochromatosis

Venesection therapy [50]

There are two phases: an induction phase and a maintenance phase. Guidelines have been devel-oped for type 1 haemochromatosis. However, they can apply to type 2, 3 and 4B.

During the induction phase, phlebotomies are performed weekly: 7 ml kg–1 without exceeding550 ml per session. The serum ferritin level is measured monthly until values move below 300 mg l–1 inmales and 200 mg l–1 in females; then bi-monthly until the goal of ferritin �50 mg l–1 is achieved. Thehaemoglobin level should always be above 11 g dl–1. The goal of the maintenance phase is to keepferritin level �50 mg l–1. Usually, one phlebotomy every 2–4 months is sufficient. Ferritin is checkedafter every two phlebotomies.

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For type 4A haemochromatosis (ferroportin disease), there is a risk of anaemia during the treat-ment. It should be monitored very carefully with regular hemoglobin assessment. A ferritin levelhigher than 50 mg l–1 can be accepted (MRI is valuable to quantify residual tissue iron excess).

In the absence of a physiological iron removal mechanism, phlebotomies are performed lifelong.Venesections are contra-indicated definitively in the case of sideroblastic anaemia or other causes ofcentral anaemia, thalassemia major and severe cardiopathy not linked to haemochromatosis. They aretemporarily contra-indicated in the case of: anaemia due to iron insufficiency <11 g dl–1, low bloodpressure <100 mmHg, lower limb arteriopathy, stroke, heart beat <50 bpm or >100 bpm, pregnancy,insufficient venous network and an impaired general condition.

Family screening

For HFE haemochromatosis, the physician has to give information to the patient (¼ the proband)about the consequences of the disease for him(her)self and for his (her) family.

Because of the potential severity of the disease and the opportunity of initiating preventivetreatment, it is advised that the patient informs his (her) family members that they should be tested.The modalities depend on the country and the health insurance system. However, only adults have tobe tested (because no treatment is considered in children). Transferrin saturation, serum ferritin andHFE genotype are recommended in siblings and children of the patient. In parents, the genotype isneeded only in the case of an increase in blood iron parameters. Another solution for children is totest the other parent. If there is no HFE mutation, children cannot be homozygous for the C282Ymutation.

Haemochromatosis arthritis

X-rays are needed for symptomatic joints. There is no evidence-based treatment for haemochro-matosis arthritis. Unfortunately, phlebotomies are most often non-effective [39,64]. Treatment is thenthe same as for osteoarthritis and CPPD. In our practice, analgesics are regularly efficient. Non-steroidalanti-inflammatory drugs are useful temporarily in the case of an acute flare. Colchicine at low doses(0.5–1 mg daily) could also be used.

Intra-articular glucocorticosteroids (at best guided with arthrography or ultrasound) are usuallyvery effective.

In some patients there is destructive arthritis, which is severely disabling. No disease-modifyinganti-rheumatic drugs (DMARDs) used in inflammatory rheumatisms, such as rheumatoid arthritis,have been studied in this indication. However, by analogy with disabling forms of CPPD, according torecent EULAR recommendations, hydroxychloroquine could be an option in very inflammatory jointdiseases more so than methotrexate because of its potential liver toxicity. IL1 blockers may bepromising but further studies are needed [93].

Osteoporosis

DXA is needed in patients with previous low energy fractures, severe iron overload, hypogonadismor classical osteoporosis fracture risks.

As for haemochromatosis rheumatism, there is no evidence-based medicine for treatment in thisparticular situation. It is not known if venesections improve BMD and decrease risk fracture. There arevery little data on this subject. In one female, BMD had improved after phlebotomies [94], but not inmales without a treatment for hypogonadism [82,95].

Guidelines for post-menopausal and male osteoporosis apply for osteoporosis in haemochroma-tosis. Patients with osteoporotic fractures or with low BMD or osteopenia with other risk factors forfracture need to be treated with approved osteoporosis medications in their country. Minimalmanagement for osteoporosis is based on: regular physical activity, dietary calcium intake of about 1 gdaily (or if impossible by water rich in calcium or a calcium drug), obtaining a 25 OH vitamin D serumlevel of 30 ng ml–1 and stopping bone toxins such as alcohol.

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Summary

In conclusion, GH is a hereditary disease expressed by iron overload in tissues. In Caucasians, it ismost often due to homozygosity of the C282Y HFE gene mutation, but other genes may be involved.In the absence of treatment by venesections, patients can develop life-threatening visceral damagesuch as liver cirrhosis and carcinoma, diabetes or heart failure. Phlebotomy treatment has beenremarkably successful in preventing these complications, but patients survive with other symptomsof the disease susceptible to impair, sometimes seriously, their quality of life. This is the case ofarthropathy and osteoporosis complicating haemochromatosis. In the wake of discoveries made inrecent years in the knowledge of iron metabolism, significant advances have been made in theunderstanding of the joint and bone damage in this disease. However, there is a need for specifictherapeutic strategies for bones and joints in these patients. In any case, it confers an important roleon rheumatologists, together with hepatologists and hematologists, in the diagnosis and manage-ment of GH.

Practice points

- In the case of unexplained joint pain or arthropathy resembling osteoarthritis, chon-drocalcinosis or CPPD, haemochromatosis should be suspected, especially in people youngerthan in the usual presentation of these diseases or in case of unusual joint location.

- Haemochromatosis arthropathy is associated with a higher rate of joint prosthesis replace-ment than in the general population and in younger people.

- Osteoporosis is a complication of iron overload and haemochromatosis. It should be assessedparticularly in patients with severe overload and other risk factors for osteoporosis or withprevious low energy fractures.

Research agenda for basic and clinical research

- Clinical and basic studies on hemochromatosis arthropathy are needed to determine thephysiological mechanisms of this complication and above all to find treatments for improvingthe quality of life of the patients.

- Clinical and basic studies on hemochromatosis osteoporosis are needed. We do not knowprecisely the fracture incidence in this disease. We do not know if venesections have an effecton the outcome of osteoporosis or which treatment for osteoporosis may be better. Finally,findings on bone loss in iron overload could be helpful for post-menopausal osteoporosis

Acknowledgements

The authors would like to thank Association Fer et foie; Fédération Française des Associations deMalades de l’Hémochromatose (FFAMH); European Grant Euro-Iron (LSH-CT-2006-037296); SociétéFrançaise de Rhumatologie (SFR); Région Bretagne. The authors also thank Vicki McNulty for her helpin preparing the manuscript.

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