357 HIP ARTHROPATHY IN GENETIC HEMOCHROMATOSIS Radiographic and Histologic Features J. S. AXFORD, A. BOMFORD, P. REVELL, 1. WATT, R. WILLIAMS, and E. B. D. HAMILTON Genetic hemochromatosis, a disorder of iron metabolism, results in the deposition of massive amounts of iron in the tissues. Arthropathy is one of a number of clinical features associated with the disease. Characteristic radiographic features in the wrist and hand have been reported, and an increased incidence of severe hip disease has been observed. In this study, hip radiographs of 112 patients with genetic hemochromatosis and arthritis were reviewed, and histologic examination of 2 femoral heads was performed. Twenty-eight of the 112 patients (25%) had evidence of arthritis of the hip joint. In 23 (82%) of the 28 patients, this feature was thought to be associated with osteoarthritis; 2 of these patients had an atypical arthropathy associated with radiolucency of the femoral head and histologic features of atypical stripping of the cartilage from the subchondral bone. These atypical features were not thought to be due to avascular necrosis, pyrophosphate-associated From the Department of Rheumatology Research, University College and Middlesex School of Medicine; the Department of Rheumatology and The Liver Unit, King s College Hospital and School of Medicine and Dentistry; the Bone and Joint Research Unit, The London Hospital Medical College, London; and the Department of Radiodiagnosis, Bristol Royal Infirmary, Bristol, UK. Supported by grants from GD Searle and Company and The Arthritis and Rheumatism Council. J. S. Axford, MD, BSc, MRCP: University College and Middlesex School of Medicine; A. Bomford, MD, MRCP: King s College Hospital and School of Medicine and Dentistry; P. Revell, MD, FRCPath: The London Hospital Medical College; I. Watt, MD, FRCR: Bristol Royal Infirmary; R. Williams, MD, FRCP, FRCS: King s College Hospital and School of Medicine and Dentistry; E. B. D. Hamilton, FRCP: King s College Hospital and School of Medicine and Dentistry. Address reprint requests to J. S. Axford, MD, BSc, MRCP, Division of Immunology, St. George s Hospital Medical School, London, SW17 ORE, UK. Submitted for publication February 14, 1990; accepted in revised form September 13, 1990. arthropathy, apatite-associated deposition arthritis, or osteoarthritis, but may be typical of genetic hemochromatosis and possibly the result of increased susceptibility to shearing forces at the bone-cartilage interface. In 5 of the 28 patients (18%), chondrocalcinosis was the sole abnormal finding on radiography. Ten of the 28 patients eventually required hip surgery, which confirms the severity of the hip disease associated with genetic hemochromatosis. Genetic hemochromatosis is a disorder of iron metabolism in which the absorption of increased amounts of iron from a normal diet leads to the deposition of massive amounts of iron in the tissues (1). Eventually, a characteristic pattern of organ dysfunction occurs, manifesting as cirrhosis, diabetes mellitus, hypogonadotropic hypogonadism, and arthropathy (2). The arthropathy is usually degenerative and noninflammatory (3), first affecting the small joints of the hands and then the larger joints of the body, such as the ankles, knees, shoulders, and hips (4-8). The clinical features of hemochromatosis arthropathy may resemble those of rheumatoid arthritis, with metacarpophalangeal joint involvement and acute attacks of synovitis, but the superficial appearance of the joint involvement may resemble that of osteoarthritis (OA) (9). The radiographic features of hemochromatosis arthropathy have been extensively described (10,l l), and although in some cases, they seem indistinguishable from those of calcium pyrophosphate dihydrate crystal deposition disease, it has been shown that the 2 disorders are not identical and that radiographs of the wrists and hands can reveal findings characteristic of hemochromatosis arthropathy (11). One of us Arthritis and Rheumatism, Vol. 34, No. 3 (March 1991)
358 AXFORD ET AL (EBDH), during the long-term followup of 112 patients with genetic hemochromatosis and arthritis, noted an increased incidence of severe disabling arthritis of the hips in these patients (6). A detailed radiologic assessment of the patients was conducted, and the results are presented here. Based on these findings and findings of histologic examination of selected cases, features of a hip arthropathy that may be typical of genetic hemochromatosis are described. PATIENTS AND METHODS The study population consisted of 112 patients (107 men and 5 women) with genetic hemochromatosis and arthritis. The average ages at the time of study were 64.2 years (range 55-73) for the women and 52.4 years (range 31-78) for the men. The diagnosis of genetic hemochromatosis was based on the presence of increased levels of serum iron and serum ferritin and increased saturation of serum transferrin (12). A liver biopsy was performed on all patients, and showed grade 3 or grade 4 siderosis (13). Standard laboratory methods were used for biochemical tests of iron indices. Histologic examinations of undecalcified plastic-embedded and decalcified paraffin-embedded bone sections were performed as described elsewhere (14,15). Standard hip radiographs were examined independently by 3 of the authors (IW, JSA, and EBDH) in a blinded study. The presence or absence of chondrocalcinosis, joint space narrowing, osteophyte formation, bone cysts, and subchondral thinning was recorded. RESULTS Findings on hip radiographs were abnormal in 28 (25%) of the 112 patients, 27 men (mean age 63 years, range 51-76.4) and 1 woman (age 62 years). The abnormal radiographic features were divided into 4 groups, and this classification, together with the distribution of these features in the study population, is shown in Table 1. Radiographic changes associated with OA were observed in 23 of the 28 patients with abnormal radiographic findings (82%). Nine patients (32%) had changes of OA alone; 12 patients had changes of OA in association with chondrocalcinosis. In 2 of these patients, the presence of pyrophosphate-associated arthropathy (hypertrophic OA) (16), as characterized by abundant osteophytosis and sclerosis (17), was noted. Table 1. Classification of 28 patients with genetic hemochromatosis according to radiologic features of the hip joints and subsequent hip surgery No. of No. requiring patients hip surgery Radiologic feature (n = 28) (n = 10) Osteoarthritis alone 9 5 Osteoarthritis plus chondrocalcinosis 12 3 Osteoarthritis plus atypical arthropathy 2 2 Chondrocalcinosis 5 0 In the remaining 2 patients, minor features of OA (hyaline cartilage thinning, rim osteophytosis, and sclerosis of the acetabular roof) were associated with atypical changes characterized by a wedge-shaped area of subchondral radiolucency within the subarticular space of the femoral head, which was not flattened and which had a distinct outline with an intact cortex. Figure 1 shows the hip radiograph of 1 of these patients (JM; aged 56 years). Five of the 28 patients (18%) had chondrocalci- Figure 1. Radiograph of the left hip of patient JM, who had genetic hemochrornatosis. The femoral head has a normal outline, and there is an area of radiolucency in the subarticular space, features associated with osteoarthritis.
HIP ARTHROPATHY IN HEMOCHROMATOSIS 359 nosis alone. Seven of the 17 patients who had chondrocalcinosis involving the hip joint had evidence of widespread deposition of calcium in other joints. In 10 patients (36%, 9 men and 1 woman) who had abnormal radiographic findings, hip surgery became necessary because of pain, limitation of movement, and decreasing mobility. Three of these patients underwent bilateral operations: 2 had bilateral total hip replacements, and 1 had a left osteotomy and a right total hip replacement. The patients mean age at the time hip surgery was first undertaken was 60.6 years (range 51-76). Of the 9 patients with features of osteoarthritis alone, 5 underwent hip operations. Both of the patients with radiographic features of an atypical arthritis underwent hip operations (bilaterally in 1). Histologic examination was performed on material from 2 patients who had total hip replacement surgery. One patient (JM) had radiographic features of atypical arthritis (Table 1 and Figure I), and the other patient (GS; aged 62 years) had features of OA alone (Table 1 and Figure 2). Gross examination of the femoral head from patient GS (Figure 3) showed apparently typical features of OA, with an area of eburnated bone, but the femoral head from patient JM showed atypical stripping of the cartilage from the subchondral bone over a large part of the articular surface (Figure 4). Histologic examination of material from patient JM revealed that the cartilage was separated from the bone at the level of the tidemark in the calcified cartilage zone (Figure 5). Moreover, the calcified cartilage zone was extremely narrow over much of the femoral head, where cartilage was still present, and in places, hyaline cartilage abutted bone, separated only by linear calcification. The cartilage was not fibrillated. Much of the cartilage had been lost from the femoral head from patient GS, and the cartilage that remained showed some fibrillation. Careful examination revealed occasional areas of horizontal splitting between cartilage and subchondral bone (Figure 6), even though the overall appearances were like those of typical OA. No crystals of calcium pyrophosphate were identified in the cartilage of either patient, and chondrocalcinosis was not present on their radiographs. Furthermore, there was no evidence of cartilage or subchondral bone necrosis. A few calcium pyrophosphate dihydrate crystals were present in the subintimal region of the synovial membrane from patient JM, and Perls staining demonstrated iron within superficial chondrocytes. Figure 2. Radiograph of the left hip of patient GS, who had genetic hemochromatosis. There is concentric hyaline cartilage thinning, joint damage, osteophytosis, and bone sclerosis, features typical of osteoarthritis. DISCUSSION Review of hip radiographs of 112 patients with genetic hemochromatosis and arthritis who were receiving long-term followup care from one of us (EBDH) revealed evidence of arthritis of the hip joint in 28 of them (25%). In 23 of these patients, joint space narrowing and, in some, destruction of the articular surface suggested the presence of OA. Interestingly, none of the patients had the characteristic subchondral cysts that have previously been described in the hands, shoulders, and ankles of patients with genetic hemochromatosis (3,4). More than half of the patients with radiographic evidence of OA also had evidence of abnormal calcium deposition in the affected joint. In 5 patients, chondrocalcinosis was the sole abnormal radiographic finding, and none of these 5 patients required hip surgery. This may suggest that chondro-
360 AXFORD ET AL Figure 3. Coronal slices of the femoral head from patient GS (viewed from the side), showing the typical appearance of osteoarthritis, with loss of cartilage and the development of small osteophytes. calcinosis is associated with a benign form of arthritis. The severity of hip disease overall, however, was demonstrated by the fact that 37% of the patients who had hip arthritis, including the 2 patients with atypical arthritis, required hip surgery, some bilaterally. This is consistent with the previous observation (6) that genetic hemochromatosis is associated with an increased incidence of severe hip disease. The association between pyrophosphate synovitis and hemochromatosis is well documented, and in 2 patients, the radiographic features were of a hypertrophic form of OA, which is considered a sign of Figure 5. Photomicrograph of the cartilage-bone interface of the femoral head from patient JM, 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). calcium pyrophosphate dihydrate crystal deposition disease (16,17). However, atypical radiographic features not hitherto associated with hemochromatosis were seen in 2 patients. These were characterized by a wedge-shaped area of radiolucency within the femoral head, which was not flattened and which had a distinct outline with an intact cortex (Figure 1). These changes are distinct from those seen in the second patient Figure 6. Photomicrograph of the cartilage-bone interface of the femoral head from patient GS, showing horizontal splitting between the cartilage and the subchondral bone (right). Note the rapid Figure 4. Hemisection of the femoral head from patient JM (viewed transition, with no definite calcified zone of cartilage, and a linear from above), showing separation of the cartilage from the underlying tidemark region (hematoxylin and eosin stained, decalcified, original bone. magnification x 300).
HIP ARTHROPATHY IN HEMOCHROMATOSIS 361 discussed (patient GS, Figure 2) and totally unlike those demonstrated in OA patients in our experience. Histologic examination of tissues from 1 of these patients with atypical radiographic changes (patient JM) revealed unusual features, consisting of stripping of the cartilage from the subchondral bone at the level of the tidemark in the calcified cartilage zone. Interestingly, histologic examination of the hip joint of patient GS, who had radiographic evidence of OA, revealed areas of horizontal splitting between cartilage and subchondral bone. It is important to note that calcium pyrophosphate crystals were not detected in the cartilage of either of these 2 patients, and were present only in small numbers in the synovial membrane of patient JM. These atypical findings were clearly not those of avascular necrosis, since the findings were confined to subchondral areas with normal adjacent trabeculae, and there was no evidence of a segmental area of infarction or subchondral reactive sclerosis. In addition, the absence of chondrocalcinosis radiographically and histologically militates against the rapidly progressive form of pyrophosphate arthropathy (16); the findings are also unlike apatite-associated deposition arthritis (18). While horizontal splits are sometimes seen in OA, they occur higher in the articular cartilage and not at the tidemark zone. There is normally a layer of calcified cartilage between the hyaline cartilage and bone, and it has been suggested that this is a transitional layer (in terms of stiffness) between the viscoelastic cartilage and the hard bone. This buffer zone was attenuated over most of the femoral head in the 2 patients described here, and the normal undulating outline between cartilage and bone was also less developed. While thinning of the calcified zone has been shown to occur with increasing age, such marked narrowing as that seen in patient JM, where separation occurred, has not been previously reported. Increased susceptibility to shearing forces at the bone-cartilage interface is one possible explanation for the splitting of the cartilage. ACKNOWLEDGMENTS We thank Professor Paul Dieppe for helpful discussion and Ann Maitland for help in preparing the manuscript. REFERENCES 1. Powell LW, Bassett ML, Halliday JW: Haemochromatosis: 1980 update. Gastroenterology 78:374381, 1980 2. Bothwell TH, Charlton RW, Motulsky AG: The metabolic basis of inherited disease, Hemochromatosis. Sixth edition. Edited by CR Scriver, AC Beaudet, WS Sly, D Valle. New York, McGraw-Hill, 1989 3. Schumacher HR: Hemochromatosis and arthritis. Arthritis Rheum 7:41-50, 1964 4. Hamilton E, Williams R, Barlow KA, Smith PM: The arthropathy of idiopathic haemochromatosis. Q J Med 37:171-182, 1968 5. Dymock IW, Hamilton EBD, Laws JW, Williams R: Clinical and radiological analysis of 63 patients with iron overload. Ann Rheum Dis 29:469-476, 1970 6. Atkins CJ, McIvor J, Smith PM, Hamilton E, Williams R: Studies in haeniochromatosis and in idiopathic chondrocalcinosis. Q J lded 34:71-82, 1970 7. Walker RJ, Dymock IW, Ansell ID, Hamilton EBD, Williams R: Synovial biopsy in haemochromatosis arthropathy. Ann Rheum Dis 31:98-102, 1972 8. Hamilton EBD, Bomford AB, Laws JW, Williams R: The natural history of arthritis in idiopathic haemochromatosis. Q J Med 50:321-329, 1981 9. Hamilton EBD: Arthritis in ochronosis, haemochromatosis and Wilson s disease, Copemans Textbook of the Rheumatic Diseases. Sixth edition. Edited by JT Scott. Edinburgh, Churchill Livingstone, 1986 10. Bywaters EGL, Hamilton EBD, Williams R: The spine in idiopathic haemochromatosis. Ann Rheum Dis 30: 453-465, 1971 11. Adamson TC, Resnick CS, Guerra J, Wint VC, Weisman MH, Resnick D: Hand and wrist arthropathies of hemochromatosis and calcium pyrophosphate deposition disease: distinct radiographic features. Radiology 1471377-381, 1983 12. Walker RJ, Williams R: Haemochromatosis and iron overload, Iron in Biochemistry and Medicine. Edited by A Jacobs, M Worwood. London, Academic Press, 1974 13. Scheur P, Williams R, Muir AR: Hepatic pathology in relatives of patients with haemochromatosis. J Pathol Bacteriol 84:53-64, 1962 14. Revell PA: Pathology of Bone. New York, Springer, 1986 15. Bradley GW, Freeman MAR, Revell PA: Resurfacing arthropathy: femoral head viability. Clin Orthop 220: 137-141, 1987 16. Resnick D, Niwayama G, editors: Diagnosis of Bone and Joint Disorders, Second edition. Philadelphia, WB Saunders, 1988 17. Dieppe PA, Alexander GJA, Jones HE, Doherty M, Scott DGI, Manhire A, Watt I: Pyrophosphate arthropathy: a clinical and radiological study of 105 cases. Ann Rheum Dis 41:271-276, 1982 18. Dieppe PA, Doherty M, Macfarlane DG, Hutton CW, Bradfield JW, Watt I: Apatite associated destructive arthritis. Br J Rheumatol 23:84-91, 1984