9 Rheumatic manifestations of haemochromatosis J. S. A X F O R D
T H E CLINICAL SYNDROMES OF HAEMOCHROMATOSIS
Haemochromatosis (HC) is a group of phenotypically heterogeneous clinical syndromes which may have a common molecular basis. They may be caused by a single abnormal regulatory protein, with disease variation occurring through several discrete amino acid substitutions (Lombard et al, 1989). It is likely that the regulatory protein coordinates cellular iron metabolism. There are at least four clinical variants of HC. 1. 2. 3. 4.
Perinatal genetic HC (Silver et al, t987): usually fatal and frequently familial. Genetic HC in young adults (Herrick et al, 1989): equal male and female occurrence, with cardiac manifestations prominent and often fatal. Classical genetic HC: predominant in middle-aged male patients and has an association with diabetes metlitus, arthritis and hypogonadism. Acquired HC: can occur secondarily to other disease, for example: chronic disorders of erythropoiesis, e.g. siderobtastic anaemia and thalassaemia alcoholic subjects with chronic liver disease excessive iron ingestion, e.g. South African Bantu
Individuals with acquired HC may become iron overloaded if they carry the HC allele (Simon, 1987) and clinically and pathologically there may be little difference between genetic and acquired HC.
CLASSICAL GENETIC HAEMOCHROMATOSIS Classical genetic haemochromatosis (GHC) is a disorder of iron storage due to an increase in intestinal iron absorption which results in progressive and massive iron deposition leading to fibrosis and organ malfunction. The liver, pancreas, heart and pituitary are commonly involved (Weintraub et al, 1988). The disease was first recorded over 100 years ago (Trousseau, 1865; Troiser, 1871; Von Recklinghausen, 1889) and was subsequently recognized as an Bailli~re's ClinicalRheumatology--
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inherited metabolic disorder (Sheldon, 1935) with a specific arthropathy (Schumacher, 1964; Hamilton et al, 1968).
Epidemiology GHC is one of the most common genetic abnormalities in the Caucasian population. The disease and carrier frequency are 0.3% and 10% respectively. The disease is 5-10 times more frequent in males and nearly 70% of patients develop their first symptoms between the ages of 40 and 60 years (Powell and Isselbacher, 1987).
Pathogenesis The normal body iron content is 3-4 g and, in advanced disease, the body may contain over 20 g of iron, which is deposited mainly in the parenchymal cells of the liver, pancreas and heart (Finlayson, 1990). The mechanism by which iron causes damage to cells and cirrhosis in the liver is not known. It may be through membrane lipid peroxidation or through the generation of superoxide anions by free iron within the cell. This may also involve liposomal disruption and enzymic autodigestion of cells. The mechanism resulting in increased iron absorption is also unknown, but a failure of the normal homeostatic mechanisms controlling iron absorption from the duodenum is probably important (Fracanzani et al, 1989; Lombard et al, 1990). There may be aberrant regulation of the transferrin receptor and ferritin molecule, as well as other proteins for iron transport and storage, in the duodenal mucosa of patients with GHC (Fracanzani et al, 1989). This would imply that there is a failure to relay information about the iron concentration to the mucosa in order to regulate iron absorption. That GHC is inherited was suggested more than 50 years ago (Sheldon, 1935) and it is now known that there is an association with the HLA Class I gene products, A3, B14 and B7 (Bomford et al, 1977; Simon, ]977). The mode of inheritance is autosomat recessive and heterozygotes do not develop clinical evidence of the disease. No specific phenotypic or genotypic marker is currently available to make a definitive diagnosis of GHC.
Clinical manifestations GHC principally results in skin pigmentation, diabetes, liver and cardiac dysfunction, arthropathy and hypogonadism.
Diagnosis The characteristic association of organ involvement should suggest the diagnosis, and laboratory investigation and imaging of the involved system should be confirmatory. Laboratory investigation may reveal the presence of rheumatoid factor together with a normal or moderately elevated erythrocyte sedimentation rate and a normal or depressed level of serum uric acid (De Seze et al, 1972). Synovial fluid examination characteristically
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shows a low white cell count, which is composed predominantly of mononuclear cells that may contain iron (Resnick and Niwayama, 1988). Definitive diagnosis is made by detecting an increase in total body iron concentration and histological demonstration of increased parenchymat iron levels. This can be achieved by the measurement of serum iron concentration, saturation of transferrin and serum ferritin level, together with liver biopsy (Figure 1). Determining the H L A type is not used for general screening because only 70% of patients with the disease are H L A A3 positive, which also occurs in 28% of the general population (Finlayson, 1990).
Figure 1. Liver: Low power view showing nodular pattern with a band of fibrous tissue (centre). There is heavy iron deposition within the liver cells of the nodule (black). (Perl's prussian blue stain.)
Treatment GHC is treated by gradual removal of the excess body iron and symptomatic therapy for organ dysfunction. Iron should be removed by phlebotomy. Chelating agents such as desferrioxamine have little place in the treatment of GHC.
Prognosis If untreated, the principal causes of death are cardiac failure, hepatocellular failure, portal hypertension and hepatocellular carcinoma. When symptomatic, the 5-year survival with treatment is approximately 90%. Malignancy can be prevented with early treatment, and family screening is therefore important.
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HAEMOCHROMATOSIS ARTHRITIS Epidemiology
About half the patients with G H C will develop arthritis (Dorfman et al, 1969; Dymock et al, 1970). Clinical features of haemochromatosis arthritis
Arthritis may be the presenting symptom of G H C (Gordon and Little, 1973; M'Seffar et al, 1977) but usually occurs after diagnosis, and is more severe in patients over 50 years of age (Hamilton et al, 1968; Dymock et al, 1970). Arthritic manifestations are diverse (De Jonge-Bok, 1987). Initially joint inflammation is minimal and presenting symptoms are of twinges of pain on flexing the small joints of the hand; in particular the second and third metacarpophalangeal joints (Dymock et al, 1970; Hamilton et al, 1981). However, an acute presentation may occur (Budiman-Mak et al, 1977). The arthritis can then progress and large joints may become involved, particularly hips, knees andshoulders, which may cause severe disability and require surgery (Axford et al, 1991). The distribution of joint involvement may resemble rheumatoid arthritis and reduced flexion at the metacarpophalangeal joints has been noted, but ulnar deviation does not occur. Superficially, however, bony swelling may develop, which has the appearance of osteoarthritis (Hamilton, 1986). Acute attacks of synovitis can occur
Figure 2. Serial radiographs of the metacarpophalangealjoints in a patient with GHC. Five years separates these radiographs, there is loss of joint space at the metacarpophalangeal articulationsand a hook-likeosteophytehas developedfrom the radial aspectof the metacarpal head of the middle finger.
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(Hamilton et al, 1968; Dymock et al, 1970), probai~ly due to calcium pyrophosphate dihydrate (CPPD) deposition, which may resemble a rheumatoid flare. At the other end of the spectrum, patients may only have mild arthralgia at night or on awakening (De Seze et al, 1972). Joint involvement has not been mentioned in most reports of juvenile onset H C (Charlton et al, 1967; Cazzola et al, 1983; Editorial, 1984). Arthritis in G H C does not appear to be an early predictor of disease, nor can it be predicted by serum iron levels alone, as patients can have elevated levels of iron without clinical arthritis. It does seem that serum transferrin saturation values correspond with the presence of arthritis (Mathews and Williams, 1987), however high saturation of transferrin may be a result of the duration of disease.
Joint imaging Haemochromatosis arthritis has three radiographic categories (Adamson et al, 1983; Axford et al, 1991): 9 Isolated chondrocalcinosis 9 Hypertrophic osteoarthritis, indistinguishable from pyrophosphate associated arthropathy 9 Disease specific changes, comprising subchondral radiolucency of the femoral head, hook-like osteophytes on the metacarpal heads and a degenerative predilection for the metacarpophalangeal joint rather than the scapholunate. Small cysts of approximately 1-3 mm diameter affecting the metacarpal heads are seen early in disease (Hamilton et al, 1968; Dymock et al, 1970) and joint surfaces can become roughened and irregular, resulting in the destruction of the articular surface (De Seze et al, 1972) (Figure 2). Sclerosis and joint narrowing may also occur and in the hip there may be the additional change of subchondral radiolucency within the subarticular space of the femoral head (Axford et al, 1991) (Figure 3). This finding in the hip is thought to be unique to GHC. Chondrocalcinosis due to CPPD deposition, has a well-documented association with GHC and is present in about two-thirds of patients (Dymock et al, 1970; Hamilton, 1986; Resnick and Niwayama, 1988). As disease progresses, the incidence and severity of CPPD deposition also increases, with knees and wrists being more frequently involved, but the hips, symphysis pubis and spine are also affected (Figure 4). CPPD deposition is not related to age nor to the amount of iron removed with treatment, and the severity in radiological progression of arthritis and CPPD deposition does not decrease or disappear with treatment (Hamilton et al, 1981). Calcification of the intervertebral discs can also occur and these changes may radiographically resemble ankylosing spondylitis (Bywaters et al, 1971) (Figure 5). The Achilles tendon and plantar fascia may be other sites of calcium deposition. There are distinct radiographic differences between the arthropathy of G H C and primary CPPD disease (Adamson et al, 1983). GHC is distinguished by:
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(a)
,(b) Figure 3. A comparison of hip radiographs from a patient with genetic haemochromatosis (a) and a patient with pyrophosphate associated arthropathy (b). In GHC there is modest overall hyaline cartilage thinning and minor osteophytosis and the striking abnormality is a zone of subchondral radiolucency in the superior pole with some adjacent sclerosis. In pyrophosphate associated arthropathy marked hypertrophic new bone formation is demonstrated with abundant osteophytosis and some subchondral sclerosis.
Figure 4. Serial knee radiographs showing chondr0calcinosis from a patient with GHC. Eleven years separate these two radiographs and during this time there has been progressive deposition of chondrocalcinosis without the development of either joint space narrowing or secondary degenerative arthritis.
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Figure 5. A radiograph of the Lumbar spine in GHC demonstrating chondrocalcinosis in the intervertebral discs.
9 more prevalent narrowing of the metacarpophalangeal joints, including those in the 4th and 5th digits 9 peculiar hook-like osteophytes on the radial aspect of the metacarpal heads 9 less prevalent separation of the scaphoid and the lunate bones These radiographic differences indicate that the arthropathy of G H C is related to other factors in addition to the presence of CPPD.
Histology Macroscopically G H C synovial tissue is brown due to iron deposition (Collins, 1951; De Seze et al, 1972) and microscopically the following are characteristic: 9 abnormal amounts of iron deposits 9 little or no signs of synovial inflammation 9 CPPD deposition
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Figure 6. High power view of synovium showing iron deposition (black) in the synovial lining cells (synoviocytes) and in underlying macrophages in the inflammatory infiltrate. (Perl's prussian blue stain.)
Figure 7. Hemisection of the femoral head showing separation of the cartilage from the underlying bone.
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Figure 8. Photomicrograph of the cartilage-bone interface of the femoral head showing separation of the cartilage (top) from the bone (bottom). Note the absence of a calcified zone of cartilage. (Hematoxylin and eosin stained, decalcified, original magnification x 300.)
Iron is found in the intimal and phagocytic cells and this is associated with intimal cell hypoplasia and villus formation (Walker et al, 1972) (Figure 6). Chronic inflammatory cell infiltration is uncommon and cartilage may be stripped from the subchondral bone at the level of the tide-mark in the calcified cartilage zone (Figure 7). This finding may be specific to GHC and caused by increased susceptibility to shearing forces at the bone cartilage interface (Axford et al, 1991) (Figure 8). Electron microscopy shows that iron is predominantly found in the lining cells rich in rough endoplasmic reticulum (Schumacher, 1972). Apatite and CPPD crystals may occur together with iron deposits (Schumacher, 1982), but there is no spatial relationship and crystals can be found in the absence of iron deposits. CPPD crystals in intervertebral discs are found in the outer and peripheral layers of the annulous fibrosis, the ligamentum flavum and also associated with microfissure formation (Bywaters et al, 1971). Pathogenesis of arthritis A defect in iron metabolism
Iron is implicated in the pathogenesis of GHC arthritis by its presence in a variety of joint tissues (Sheldon, 1935; De Seze et al, 1966; Muirden and Senator, 1968; Schumacher, 1972; 1982) but there is no correlation between the extent of iron deposition and the histological and radiological changes. Furthermore, treatment has little effect on arthritic symptoms (Dymock et al, 1970).
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Ferric salts have been found to promote crystal growth and to inhibit the removal of the crystals once they have been formed (Hearn et al, 1978; Hearn and Russell, 1980; Hamilton, 1986). This has been tested in vivo by the induction of synovial haemosiderosis in rabbit knees through the injection of blood followed by measurement of the clearance rate of CPPD crystals from the joints. Synovial haemosiderosis was found to reduce significantly their clearance, suggesting that intracellular pyrophosphates are inhibited by iron (McCarty et al, 1981; Hamilton, 1986). Whether or not the arthritis of GHC is specific for iron overload is debatable (Collins, 1951; Hamilton, 1986). Features specific to haemochromatosis have been reported in the hands and hips (Resnick and Niwayama, 1988; Axford et al, 1991) and similarity to arthritis associated with other diseases is also evident (Martell et al, 1970; Berry and Miller, 1973; Resnick and Utsinger, 1974; Sella and Goodman, 1975; Hamilton, 1986). Furthermore, increased deposition of iron in the synovial tissue is also observed in a variety of other disorders, namely rheumatoid arthritis (Muirden and Senator, 1968; Hamilton, 1976), degenerative arthritis (Schumacher, 1972), pigmented vilonodular synovitis (Muirden and Senator, 1968; Wyllie, 1969), haemophilia (Key, 1932) and haemarthrosis (Roy and Ghadially, 1966), which have contrasting pathological lesions. There is also no morphological relationship between crystal deposition and iron (Schumacher, 1982). On balance, it may be that iron deposition can trigger a number of pathological events, for example free radical generation and crystal deposition, which result in a range of clinical manifestations. In some instances, the generation of free radicals may cause changes in immunoglobulin carbohydrate composition that could result in immune complex formation and inflammation (Lunec et al, 1985; Axford and Hay, 1991), which are subsequently superimposed upon changes due to CPPD deposition.
A cartilage defect It is possible that there is a metabolic abnormality, independent of the disorder of iron metabolism, and responsible for alteration in cartilage matrix (De Seze et al, 1972). The arthritis of HC is similar to that seen in other metabolic disorders, such as hyperparathyroidism, ochronosis and Wilson's disease (Hamilton, 1976) and it may be that there are two coexisting inheritable traits, G H C and arthropathy (Schumacher, 1964).
An immunological defect There is evidence to show that patients with acquired HC have a variety of immunological abnormalities (De Sousa, 1989), but there is still uncertainty as to whether this is a primary dysfunction or secondary to the treatment, blood transfusion and splenectomy, these patients receive. Superoxide anion production from neutrophils has been shown to be reduced (Martino et al, 1984; De Sousa, 1989) and there seems to be both a rectuction and
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expansion of CD4 and CD8 positive T cells respectively (Kapadia et al, 1980; Dwyer et al, 1987). There is no evidence to suggest that similar changes are found in patients with GHC (De Sousa, 1989). Also, ferritin secretion from human mononuclear cells is thought to be under the control of the major histocompatibility complex gene products and reduced secretion is associated with the presence of HLA A3 gene products in acquired HC (Pollack et al, 1983). This is, of course, one of the gene products associated with GHC and it has been suggested that a similar abnormality of the macrophage system may exist in both these diseases (De Sousa, 1989). What is of interest, therefore, is that, in marked contrast to the heavy iron overload in parenchymal cells, the amount of demonstrable intracellular iron in macrophages, both peripheral and gut related, is minimal in GHC until the late stages of the disease (Astalda et al, 1966; Brink et al, 1976); despite the normal synthesis of ferritin by macrophages (Basset et al, 1982).
OSTEOPOROSIS IN HAEMOCHROMATOSIS
Abnormalities of bone metabolism associated with GHC have been well described (Delbarre, 1960; Jaffres, 1963; Wardle and Patton, 1969; Pawlotsky et al, 1979; Diamond et al, 1989) and a significant decrease in bone density is seen, particularly when hypogonadism is present. The incidence of osteoporosis varies in genetic and acquired HC from 25% to about 50% (Schumacher, 1964; Hamilton et al, 1968; De Seze et al, 1972) and the low levels of serum free testosterone rather than calciotropic hormone abnormalities seem to be aetiological factors in reducing bone mass (Diamond et al, 1989). Serum calcium, phosphorus and alkaline phosphatase levels are usually normal and urinary and fecal calcium excretion may be increased. Calcium kinetic studies have pointed to a deficiency in calcium absorption (De Seze et at, 1972). Osteoblastic function is significantly greater in venesected than in non-venesected patients, although the trabecular bone volumes of these two groups are similar (Diamond et al, 1989). Clinically, the osteoporosis is usually asymptomatic and may be localized to the hands.
SUMMARY
Haemochromatosis (HC) is a group of phenotypically heterogeneous clinical syndromes, which may have a common molecular basis. Classical genetic haemochromatosis (GHC) is one of these syndromes and is a disorder of iron storage due to an increase in intestinal iron absorption, which results in progressive and massive iron deposition leading to fibrosis and organ malfunction. The liver, pancreas, heart and pituitary are commonly involved. There is a specific arthropathy and an association with osteoporosis.
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Clinically, t h e a r t h r o p a t h y m a y r e s e m b l e r h e u m a t o i d arthritis, with a c u t e a t t a c k s o f i n f l a m m a t i o n a s s o c i a t e d with b i l a t e r a l d e s t r u c t i o n of the m e t a c a r p o p h a l a n g e a l joints. H o w e v e r , b o n y j o i n t swelling m a y occur, suggestive o f o s t e o a r t h r i t i s . H i p arthritis m a y b e u n d u l y s e v e r e a n d disabling, H a e m o c h r o m a t o s i s arthritis is c o m p o s e d o f t h r e e r a d i o g r a p h i c c a t e g o r i e s : i s o l a t e d c h o n d r o c a l c i n o s i s , h y p e r t r o p h i c o s t e o a r t h r i t i s which is i n d i s t i n g u i s h a b l e f r o m p y r o p h o s p h a t e a s s o c i a t e d a r t h r o p a t h y , a n d d i s e a s e specific c h a n g e s such as s u b c h o n d r a l r a d i o l u c e n c y of t h e f e m o r a l h e a d , h o o k - l i k e o s t e o p h y t e s o n the m e t a c a r p a l h e a d s a n d a d e g e n e r a t i v e p r e d i l e c t i o n for the metacarpophalangeal joint rather than the scapholunate. T h e c h a r a c t e r i s t i c h i s t o l o g i c a l changes are: a b n o r m a l a m o u n t s of i r o n d e p o s i t s , little o r no signs o f s y n o v i a l i n f l a m m a t i o n a n d C P P D d e p o s i t i o n . Subchondral radiolucency of the femoral head and atypical stripping of the c a r t i l a g e f r o m t h e s u b c h o n d r a l b o n e are t h o u g h t to b e specific r a d i o g r a p h i c a n d h i s t o l o g i c a l c h a n g e s o f H C . T h e p a t h o g e n e s i s of H C arthritis has b e e n a s s o c i a t e d with the p r e s e n c e of i r o n in j o i n t tissue, a d e f e c t in cartilage m e t a b o l i s m a n d i m m u n o l o g i c a l dysfunction. T r e a t m e n t has little effect on clinical, r a d i o l o g i c a l o r h i s t o l o g i c a l p r o g r e s s i o n .
Acknowledgements The author would like to thank Drs E. B. D. Hamilton, A. Bomford, I. Watt and P. Revell for providing radiographs and photomicrographs from patients under their care and for constructive review of the manuscript. Mrs A. Alavi and Miss A. McSorley are also thanked for diligent editorial assistance.
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haemochromatosis arthropathy. Histological findings and iron deposition in relation to total body iron overload. Annals of the Rheumatic Diseases 31: 98-102. Wardle EN & Patton JT (1969) Bone and joint changes in haemochromatosis. Annals o f the Rheumatic Diseases 28: 15. Weintraub LR, Edwards CQ & Krikker M (eds) (1988) Hemochromatosis. Proceedings of the first international conference of the New York Academy of Sciences. Annals of the New York Academy o f Sciences 526: 1-370. Wyllie JC (1969) The stromal cell reaction of pigmented villonodular synovitis: an electron microscopic study. Arthritis and Rheumatism 12: 205.
T H E CLINICAL SYNDROMES OF HAEMOCHROMATOSIS
Haemochromatosis (HC) is a group of phenotypically heterogeneous clinical syndromes which may have a common molecular basis. They may be caused by a single abnormal regulatory protein, with disease variation occurring through several discrete amino acid substitutions (Lombard et al, 1989). It is likely that the regulatory protein coordinates cellular iron metabolism. There are at least four clinical variants of HC. 1. 2. 3. 4.
Perinatal genetic HC (Silver et al, t987): usually fatal and frequently familial. Genetic HC in young adults (Herrick et al, 1989): equal male and female occurrence, with cardiac manifestations prominent and often fatal. Classical genetic HC: predominant in middle-aged male patients and has an association with diabetes metlitus, arthritis and hypogonadism. Acquired HC: can occur secondarily to other disease, for example: chronic disorders of erythropoiesis, e.g. siderobtastic anaemia and thalassaemia alcoholic subjects with chronic liver disease excessive iron ingestion, e.g. South African Bantu
Individuals with acquired HC may become iron overloaded if they carry the HC allele (Simon, 1987) and clinically and pathologically there may be little difference between genetic and acquired HC.
CLASSICAL GENETIC HAEMOCHROMATOSIS Classical genetic haemochromatosis (GHC) is a disorder of iron storage due to an increase in intestinal iron absorption which results in progressive and massive iron deposition leading to fibrosis and organ malfunction. The liver, pancreas, heart and pituitary are commonly involved (Weintraub et al, 1988). The disease was first recorded over 100 years ago (Trousseau, 1865; Troiser, 1871; Von Recklinghausen, 1889) and was subsequently recognized as an Bailli~re's ClinicalRheumatology--
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inherited metabolic disorder (Sheldon, 1935) with a specific arthropathy (Schumacher, 1964; Hamilton et al, 1968).
Epidemiology GHC is one of the most common genetic abnormalities in the Caucasian population. The disease and carrier frequency are 0.3% and 10% respectively. The disease is 5-10 times more frequent in males and nearly 70% of patients develop their first symptoms between the ages of 40 and 60 years (Powell and Isselbacher, 1987).
Pathogenesis The normal body iron content is 3-4 g and, in advanced disease, the body may contain over 20 g of iron, which is deposited mainly in the parenchymal cells of the liver, pancreas and heart (Finlayson, 1990). The mechanism by which iron causes damage to cells and cirrhosis in the liver is not known. It may be through membrane lipid peroxidation or through the generation of superoxide anions by free iron within the cell. This may also involve liposomal disruption and enzymic autodigestion of cells. The mechanism resulting in increased iron absorption is also unknown, but a failure of the normal homeostatic mechanisms controlling iron absorption from the duodenum is probably important (Fracanzani et al, 1989; Lombard et al, 1990). There may be aberrant regulation of the transferrin receptor and ferritin molecule, as well as other proteins for iron transport and storage, in the duodenal mucosa of patients with GHC (Fracanzani et al, 1989). This would imply that there is a failure to relay information about the iron concentration to the mucosa in order to regulate iron absorption. That GHC is inherited was suggested more than 50 years ago (Sheldon, 1935) and it is now known that there is an association with the HLA Class I gene products, A3, B14 and B7 (Bomford et al, 1977; Simon, ]977). The mode of inheritance is autosomat recessive and heterozygotes do not develop clinical evidence of the disease. No specific phenotypic or genotypic marker is currently available to make a definitive diagnosis of GHC.
Clinical manifestations GHC principally results in skin pigmentation, diabetes, liver and cardiac dysfunction, arthropathy and hypogonadism.
Diagnosis The characteristic association of organ involvement should suggest the diagnosis, and laboratory investigation and imaging of the involved system should be confirmatory. Laboratory investigation may reveal the presence of rheumatoid factor together with a normal or moderately elevated erythrocyte sedimentation rate and a normal or depressed level of serum uric acid (De Seze et al, 1972). Synovial fluid examination characteristically
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shows a low white cell count, which is composed predominantly of mononuclear cells that may contain iron (Resnick and Niwayama, 1988). Definitive diagnosis is made by detecting an increase in total body iron concentration and histological demonstration of increased parenchymat iron levels. This can be achieved by the measurement of serum iron concentration, saturation of transferrin and serum ferritin level, together with liver biopsy (Figure 1). Determining the H L A type is not used for general screening because only 70% of patients with the disease are H L A A3 positive, which also occurs in 28% of the general population (Finlayson, 1990).
Figure 1. Liver: Low power view showing nodular pattern with a band of fibrous tissue (centre). There is heavy iron deposition within the liver cells of the nodule (black). (Perl's prussian blue stain.)
Treatment GHC is treated by gradual removal of the excess body iron and symptomatic therapy for organ dysfunction. Iron should be removed by phlebotomy. Chelating agents such as desferrioxamine have little place in the treatment of GHC.
Prognosis If untreated, the principal causes of death are cardiac failure, hepatocellular failure, portal hypertension and hepatocellular carcinoma. When symptomatic, the 5-year survival with treatment is approximately 90%. Malignancy can be prevented with early treatment, and family screening is therefore important.
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HAEMOCHROMATOSIS ARTHRITIS Epidemiology
About half the patients with G H C will develop arthritis (Dorfman et al, 1969; Dymock et al, 1970). Clinical features of haemochromatosis arthritis
Arthritis may be the presenting symptom of G H C (Gordon and Little, 1973; M'Seffar et al, 1977) but usually occurs after diagnosis, and is more severe in patients over 50 years of age (Hamilton et al, 1968; Dymock et al, 1970). Arthritic manifestations are diverse (De Jonge-Bok, 1987). Initially joint inflammation is minimal and presenting symptoms are of twinges of pain on flexing the small joints of the hand; in particular the second and third metacarpophalangeal joints (Dymock et al, 1970; Hamilton et al, 1981). However, an acute presentation may occur (Budiman-Mak et al, 1977). The arthritis can then progress and large joints may become involved, particularly hips, knees andshoulders, which may cause severe disability and require surgery (Axford et al, 1991). The distribution of joint involvement may resemble rheumatoid arthritis and reduced flexion at the metacarpophalangeal joints has been noted, but ulnar deviation does not occur. Superficially, however, bony swelling may develop, which has the appearance of osteoarthritis (Hamilton, 1986). Acute attacks of synovitis can occur
Figure 2. Serial radiographs of the metacarpophalangealjoints in a patient with GHC. Five years separates these radiographs, there is loss of joint space at the metacarpophalangeal articulationsand a hook-likeosteophytehas developedfrom the radial aspectof the metacarpal head of the middle finger.
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(Hamilton et al, 1968; Dymock et al, 1970), probai~ly due to calcium pyrophosphate dihydrate (CPPD) deposition, which may resemble a rheumatoid flare. At the other end of the spectrum, patients may only have mild arthralgia at night or on awakening (De Seze et al, 1972). Joint involvement has not been mentioned in most reports of juvenile onset H C (Charlton et al, 1967; Cazzola et al, 1983; Editorial, 1984). Arthritis in G H C does not appear to be an early predictor of disease, nor can it be predicted by serum iron levels alone, as patients can have elevated levels of iron without clinical arthritis. It does seem that serum transferrin saturation values correspond with the presence of arthritis (Mathews and Williams, 1987), however high saturation of transferrin may be a result of the duration of disease.
Joint imaging Haemochromatosis arthritis has three radiographic categories (Adamson et al, 1983; Axford et al, 1991): 9 Isolated chondrocalcinosis 9 Hypertrophic osteoarthritis, indistinguishable from pyrophosphate associated arthropathy 9 Disease specific changes, comprising subchondral radiolucency of the femoral head, hook-like osteophytes on the metacarpal heads and a degenerative predilection for the metacarpophalangeal joint rather than the scapholunate. Small cysts of approximately 1-3 mm diameter affecting the metacarpal heads are seen early in disease (Hamilton et al, 1968; Dymock et al, 1970) and joint surfaces can become roughened and irregular, resulting in the destruction of the articular surface (De Seze et al, 1972) (Figure 2). Sclerosis and joint narrowing may also occur and in the hip there may be the additional change of subchondral radiolucency within the subarticular space of the femoral head (Axford et al, 1991) (Figure 3). This finding in the hip is thought to be unique to GHC. Chondrocalcinosis due to CPPD deposition, has a well-documented association with GHC and is present in about two-thirds of patients (Dymock et al, 1970; Hamilton, 1986; Resnick and Niwayama, 1988). As disease progresses, the incidence and severity of CPPD deposition also increases, with knees and wrists being more frequently involved, but the hips, symphysis pubis and spine are also affected (Figure 4). CPPD deposition is not related to age nor to the amount of iron removed with treatment, and the severity in radiological progression of arthritis and CPPD deposition does not decrease or disappear with treatment (Hamilton et al, 1981). Calcification of the intervertebral discs can also occur and these changes may radiographically resemble ankylosing spondylitis (Bywaters et al, 1971) (Figure 5). The Achilles tendon and plantar fascia may be other sites of calcium deposition. There are distinct radiographic differences between the arthropathy of G H C and primary CPPD disease (Adamson et al, 1983). GHC is distinguished by:
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(a)
,(b) Figure 3. A comparison of hip radiographs from a patient with genetic haemochromatosis (a) and a patient with pyrophosphate associated arthropathy (b). In GHC there is modest overall hyaline cartilage thinning and minor osteophytosis and the striking abnormality is a zone of subchondral radiolucency in the superior pole with some adjacent sclerosis. In pyrophosphate associated arthropathy marked hypertrophic new bone formation is demonstrated with abundant osteophytosis and some subchondral sclerosis.
Figure 4. Serial knee radiographs showing chondr0calcinosis from a patient with GHC. Eleven years separate these two radiographs and during this time there has been progressive deposition of chondrocalcinosis without the development of either joint space narrowing or secondary degenerative arthritis.
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Figure 5. A radiograph of the Lumbar spine in GHC demonstrating chondrocalcinosis in the intervertebral discs.
9 more prevalent narrowing of the metacarpophalangeal joints, including those in the 4th and 5th digits 9 peculiar hook-like osteophytes on the radial aspect of the metacarpal heads 9 less prevalent separation of the scaphoid and the lunate bones These radiographic differences indicate that the arthropathy of G H C is related to other factors in addition to the presence of CPPD.
Histology Macroscopically G H C synovial tissue is brown due to iron deposition (Collins, 1951; De Seze et al, 1972) and microscopically the following are characteristic: 9 abnormal amounts of iron deposits 9 little or no signs of synovial inflammation 9 CPPD deposition
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Figure 6. High power view of synovium showing iron deposition (black) in the synovial lining cells (synoviocytes) and in underlying macrophages in the inflammatory infiltrate. (Perl's prussian blue stain.)
Figure 7. Hemisection of the femoral head showing separation of the cartilage from the underlying bone.
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Figure 8. Photomicrograph of the cartilage-bone interface of the femoral head showing separation of the cartilage (top) from the bone (bottom). Note the absence of a calcified zone of cartilage. (Hematoxylin and eosin stained, decalcified, original magnification x 300.)
Iron is found in the intimal and phagocytic cells and this is associated with intimal cell hypoplasia and villus formation (Walker et al, 1972) (Figure 6). Chronic inflammatory cell infiltration is uncommon and cartilage may be stripped from the subchondral bone at the level of the tide-mark in the calcified cartilage zone (Figure 7). This finding may be specific to GHC and caused by increased susceptibility to shearing forces at the bone cartilage interface (Axford et al, 1991) (Figure 8). Electron microscopy shows that iron is predominantly found in the lining cells rich in rough endoplasmic reticulum (Schumacher, 1972). Apatite and CPPD crystals may occur together with iron deposits (Schumacher, 1982), but there is no spatial relationship and crystals can be found in the absence of iron deposits. CPPD crystals in intervertebral discs are found in the outer and peripheral layers of the annulous fibrosis, the ligamentum flavum and also associated with microfissure formation (Bywaters et al, 1971). Pathogenesis of arthritis A defect in iron metabolism
Iron is implicated in the pathogenesis of GHC arthritis by its presence in a variety of joint tissues (Sheldon, 1935; De Seze et al, 1966; Muirden and Senator, 1968; Schumacher, 1972; 1982) but there is no correlation between the extent of iron deposition and the histological and radiological changes. Furthermore, treatment has little effect on arthritic symptoms (Dymock et al, 1970).
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Ferric salts have been found to promote crystal growth and to inhibit the removal of the crystals once they have been formed (Hearn et al, 1978; Hearn and Russell, 1980; Hamilton, 1986). This has been tested in vivo by the induction of synovial haemosiderosis in rabbit knees through the injection of blood followed by measurement of the clearance rate of CPPD crystals from the joints. Synovial haemosiderosis was found to reduce significantly their clearance, suggesting that intracellular pyrophosphates are inhibited by iron (McCarty et al, 1981; Hamilton, 1986). Whether or not the arthritis of GHC is specific for iron overload is debatable (Collins, 1951; Hamilton, 1986). Features specific to haemochromatosis have been reported in the hands and hips (Resnick and Niwayama, 1988; Axford et al, 1991) and similarity to arthritis associated with other diseases is also evident (Martell et al, 1970; Berry and Miller, 1973; Resnick and Utsinger, 1974; Sella and Goodman, 1975; Hamilton, 1986). Furthermore, increased deposition of iron in the synovial tissue is also observed in a variety of other disorders, namely rheumatoid arthritis (Muirden and Senator, 1968; Hamilton, 1976), degenerative arthritis (Schumacher, 1972), pigmented vilonodular synovitis (Muirden and Senator, 1968; Wyllie, 1969), haemophilia (Key, 1932) and haemarthrosis (Roy and Ghadially, 1966), which have contrasting pathological lesions. There is also no morphological relationship between crystal deposition and iron (Schumacher, 1982). On balance, it may be that iron deposition can trigger a number of pathological events, for example free radical generation and crystal deposition, which result in a range of clinical manifestations. In some instances, the generation of free radicals may cause changes in immunoglobulin carbohydrate composition that could result in immune complex formation and inflammation (Lunec et al, 1985; Axford and Hay, 1991), which are subsequently superimposed upon changes due to CPPD deposition.
A cartilage defect It is possible that there is a metabolic abnormality, independent of the disorder of iron metabolism, and responsible for alteration in cartilage matrix (De Seze et al, 1972). The arthritis of HC is similar to that seen in other metabolic disorders, such as hyperparathyroidism, ochronosis and Wilson's disease (Hamilton, 1976) and it may be that there are two coexisting inheritable traits, G H C and arthropathy (Schumacher, 1964).
An immunological defect There is evidence to show that patients with acquired HC have a variety of immunological abnormalities (De Sousa, 1989), but there is still uncertainty as to whether this is a primary dysfunction or secondary to the treatment, blood transfusion and splenectomy, these patients receive. Superoxide anion production from neutrophils has been shown to be reduced (Martino et al, 1984; De Sousa, 1989) and there seems to be both a rectuction and
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expansion of CD4 and CD8 positive T cells respectively (Kapadia et al, 1980; Dwyer et al, 1987). There is no evidence to suggest that similar changes are found in patients with GHC (De Sousa, 1989). Also, ferritin secretion from human mononuclear cells is thought to be under the control of the major histocompatibility complex gene products and reduced secretion is associated with the presence of HLA A3 gene products in acquired HC (Pollack et al, 1983). This is, of course, one of the gene products associated with GHC and it has been suggested that a similar abnormality of the macrophage system may exist in both these diseases (De Sousa, 1989). What is of interest, therefore, is that, in marked contrast to the heavy iron overload in parenchymal cells, the amount of demonstrable intracellular iron in macrophages, both peripheral and gut related, is minimal in GHC until the late stages of the disease (Astalda et al, 1966; Brink et al, 1976); despite the normal synthesis of ferritin by macrophages (Basset et al, 1982).
OSTEOPOROSIS IN HAEMOCHROMATOSIS
Abnormalities of bone metabolism associated with GHC have been well described (Delbarre, 1960; Jaffres, 1963; Wardle and Patton, 1969; Pawlotsky et al, 1979; Diamond et al, 1989) and a significant decrease in bone density is seen, particularly when hypogonadism is present. The incidence of osteoporosis varies in genetic and acquired HC from 25% to about 50% (Schumacher, 1964; Hamilton et al, 1968; De Seze et al, 1972) and the low levels of serum free testosterone rather than calciotropic hormone abnormalities seem to be aetiological factors in reducing bone mass (Diamond et al, 1989). Serum calcium, phosphorus and alkaline phosphatase levels are usually normal and urinary and fecal calcium excretion may be increased. Calcium kinetic studies have pointed to a deficiency in calcium absorption (De Seze et at, 1972). Osteoblastic function is significantly greater in venesected than in non-venesected patients, although the trabecular bone volumes of these two groups are similar (Diamond et al, 1989). Clinically, the osteoporosis is usually asymptomatic and may be localized to the hands.
SUMMARY
Haemochromatosis (HC) is a group of phenotypically heterogeneous clinical syndromes, which may have a common molecular basis. Classical genetic haemochromatosis (GHC) is one of these syndromes and is a disorder of iron storage due to an increase in intestinal iron absorption, which results in progressive and massive iron deposition leading to fibrosis and organ malfunction. The liver, pancreas, heart and pituitary are commonly involved. There is a specific arthropathy and an association with osteoporosis.
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Clinically, t h e a r t h r o p a t h y m a y r e s e m b l e r h e u m a t o i d arthritis, with a c u t e a t t a c k s o f i n f l a m m a t i o n a s s o c i a t e d with b i l a t e r a l d e s t r u c t i o n of the m e t a c a r p o p h a l a n g e a l joints. H o w e v e r , b o n y j o i n t swelling m a y occur, suggestive o f o s t e o a r t h r i t i s . H i p arthritis m a y b e u n d u l y s e v e r e a n d disabling, H a e m o c h r o m a t o s i s arthritis is c o m p o s e d o f t h r e e r a d i o g r a p h i c c a t e g o r i e s : i s o l a t e d c h o n d r o c a l c i n o s i s , h y p e r t r o p h i c o s t e o a r t h r i t i s which is i n d i s t i n g u i s h a b l e f r o m p y r o p h o s p h a t e a s s o c i a t e d a r t h r o p a t h y , a n d d i s e a s e specific c h a n g e s such as s u b c h o n d r a l r a d i o l u c e n c y of t h e f e m o r a l h e a d , h o o k - l i k e o s t e o p h y t e s o n the m e t a c a r p a l h e a d s a n d a d e g e n e r a t i v e p r e d i l e c t i o n for the metacarpophalangeal joint rather than the scapholunate. T h e c h a r a c t e r i s t i c h i s t o l o g i c a l changes are: a b n o r m a l a m o u n t s of i r o n d e p o s i t s , little o r no signs o f s y n o v i a l i n f l a m m a t i o n a n d C P P D d e p o s i t i o n . Subchondral radiolucency of the femoral head and atypical stripping of the c a r t i l a g e f r o m t h e s u b c h o n d r a l b o n e are t h o u g h t to b e specific r a d i o g r a p h i c a n d h i s t o l o g i c a l c h a n g e s o f H C . T h e p a t h o g e n e s i s of H C arthritis has b e e n a s s o c i a t e d with the p r e s e n c e of i r o n in j o i n t tissue, a d e f e c t in cartilage m e t a b o l i s m a n d i m m u n o l o g i c a l dysfunction. T r e a t m e n t has little effect on clinical, r a d i o l o g i c a l o r h i s t o l o g i c a l p r o g r e s s i o n .
Acknowledgements The author would like to thank Drs E. B. D. Hamilton, A. Bomford, I. Watt and P. Revell for providing radiographs and photomicrographs from patients under their care and for constructive review of the manuscript. Mrs A. Alavi and Miss A. McSorley are also thanked for diligent editorial assistance.
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