Diseases associated with calcium pyrophosphate deposition disease

Diseases Associated With Calcium Pyrophosphate Deposition Disease

By Adrian C. Jones, Alexis J. Chuck, Eleanor A. Arie, Desmond J. Green,

and Michael Doherty

Although many metabolic and endocrine diseases have been reported to predispose to calcium pyrophosphate dihydrate crystal deposition, the validity of many of these associations remains unclear. A critical review of the literature relating to these associations, with illustra- tive cases and data derived from the authors’ own experience, is presented. It is concluded that there is good evidence to associate hypophosphatasia, hypomagnesemia, and hyperparathyroidism with chondrocalcinosis and acute attacks of “pseudogout.” Meta-analysis also suggests a small but significant association between hypothyroidism and chondrocalcinosis.

D EPOSITION OF calcium pyrophosphate dihydrate (CPPD) crystals within hyaline

cartilage and fibrocartilage, “chondrocalcinosis” (CC), may be asymptomatic or associated with acute crystal synovitis or chronic arthropathy.1-5 The formation of CPPD crystals involves both the “seed” (the product of calcium and inorganic pyrophosphate [PPi]) and the “soil” (the matrix in which the crystals form and grow).h Both components could be affected by many factors, including metabolic and endocrine disease, and a number of such diseases have been associated with CPPD crystal deposition. How- ever, CPPD deposition is also associated with gender,’ structural damage,8-10 and osteoarthritis (OA),’ and isolated CPPD deposition is a

From the Rheumatology Unit, City Hospital, Nottingham, England; the Drybum Hospital, Durham, England; and the Royal Hospital and Home, Putney, England.

Supported in part by the Arthritis and Rheumatism Council. Adrian C. Jones, MRCP: Research Fellow, Rheumatology

Unit, City Hospital, Nottingham; Alexis J. Chuck, MRCP:

Consultant Rheumatologist, Dryburn Hospital, Durham; Eleanor A. Arie, MRCP: Consultant Rheumatologist, Royal Hospital and Home, Putney; Desmond J. Green, FRCR:

Consultant Radiologist, City Hospital, Nottingham; Michael

Doherty, MD: Senior Lecturer, Rheumatology Unit, City Hospital, Nottingham.

Address reprint requests to Adrian C. Jones, MRCP, Rheumo- tology Unit, City Hospital, Nottingham NG5 IPB, England.

Copyright 0 1992 by U! B. Saunders Company 0049.0172/9212203-0006$5.OOlO

Hemochromatosis stands alone in clearly associ- ating not only with chondrocalcinosis but also with structural change and chronic arthropathy. The biochemical mechanisms that may produce these various associations are discussed. Recom- mendations are made concerning appropriate screening for metabolic and endocrine disease in patients with chondrocalcinosis. Copyright 0 1992 by W. B. Saunders Company

INDEX WORDS: Chondrocalcinosis; calcium pyrophosphate dihydrate; endocrine disease; metabolic disease.

common finding in aging but otherwise normal joint tissues. 2,7~11~12 Therefore, distinguishing true from spurious associations is difficult.“-”

Two approaches may be used to determine associations between diseases. For common diseases, case-control studies or large population surveys with complete ascertainment of the two diseases are necessary.‘” For less common diseases, unusual features such as young age of onset or severity may suffice.

This review will consider the prevalence of CC in the general population, consider the evidence for metabolic and endocrine disease associations, and discuss the various etiopatho- genetic mechanisms that have been proposed.

Because terminology of CPPD-related diseases is not yet standardized, we shall adopt the following conventions: chondrocalcinosis, radiographic or histological calcification of fibrocartilage or hyaline cartilage; pseudogout, acute CPPD crystal-associated synovitis; andpyrophos- phate arthropathy (PA), structural arthropathy associated with intraarticular CPPD crystal deposition (with or without associated CC).

NORMAL POPULATIONS

A number of techniques have been used in an attempt to determine the frequency of CC in the general population. These include postmor- tem studies,4.‘2.17 examination of joint tissue removed at surgery,i8xr9 and radiographic sur-

188 Seminars in Arthritis and Rheumatism, Vol22, No 3 (December), 1992: pp 188-202

DISEASES ASSOCIATED WITH CPPD CRYSTALS 189

veys.7,11,13,20-44 1 n Nottingham, we have conducted two random radiographic surveys of patients, including (1) 138 patients attending general medical clinics and (2) 96 geriatric inpatients. In both studies, patients with inflam- matory joint disease, diabetes mellitus, current corticosteroid therapy, or neoplasia were excluded. The findings of these surveys are shown in Table 1.

Comparisons between surveys are hampered by differences in radiographic technique,16,20- 22,45 patient selection differences,21~22~25 small sample size,7 and choice of joints examined.16~21~22 Despite these difficulties, there is broad agree- ment in the data.

CC occurs in approximately 5% to 10% of adults (7% in the Nottingham 138-patient survey). CC shows a marked increase with age, with a prevalence as high as 30% in those older than 75 years7 (32% in the Nottingham inpatient survey). It is apparent therefore that age must be accounted for as a confounding factor in any study relating to CC.

Conflicting evidence is available concerning predisposition of gender. Most studies suggest a female preponderance, although there have been exceptions. Such contradictory results may arise from differences in sample selection; it has been suggested that males are more likely to have pseudogout. 21,37,46 However, the best pres- ently available data confirm a female preponderance,7,40,47 with an estimated relative risk of 1.33 (95% confidence interval [CI], 0.93 to 1.92).7

The proposed association between CC and OA has now been confirmed by a large population study.7 However, relative risk is small (1.52 [95% CI, 1.03 to 3.17]),7 and causality is uncertain.7,19 Local joint damage may also predispose

Table 1: Prevalence of Chondrocalcinosis of the Knees in the Two Nottingham Surveys

Age (vr)

Clinic Patients (n = 138)

Inpatients (n = 98)

Overall (n = 234)

l/8 (13%) 30/88 (34%) 31/96 (32%)

NOTE. Data represent number of patients with chondrocalcino-

sis/total number of patients sampled.

to local CPPD deposition,s-10 trauma appearing to induce premature CC in otherwise predisposed individuals.8 The inverse relationship between rheumatoid arthritis (RA) and CC suggests that factors other than joint damage per se, for example the OA process, are also important.42148

Knowledge of ethnic variation in predisposition to CC is limited. Apart from an increased prevalence in Tunisian Muslims compared with Tunisian Jews,43 direct comparisons are lacking. Familial cases are well described,2,34,49-54 with HLA linkage demonstrated in some34,54 but not all pedigrees. 50-53 The role of genetic factors in sporadic CC is unknown.

PUTATIVE METABOLIC AND ENDOCRINE DISEASE ASSOCIATIONS

Hypomagnesemia

Numerous case reports provide convincing evidence for an association between chronic hypomagnesemia and CC.15,s5-65 Reported cases occur in young patients (mean age, 40 years; range, 15 to 59 years), often show florid polyar- titular CC, and are associated with multiple episodes of pseudogout. Interestingly, PA does not seem to be a feature. The two cases reported here, assessed in our unit, are similar to previously reported cases. Both were associated with renal wasting of magnesium, in one case with associated renal potassium wasting.

Case 1. A 50-year-old woman had a l-year history of recurrent episodes of pseudogout of the right knee, confirmed by identification of synovial fluid CPPD crystals. There was. no accompanying structural arthropathy, and radiographs showed florid, polyarticular CC. Investi- gation showed persistent hypomagnesemia (0.5 to 0.65 mmol/L, normal range, 0.7 to 1.0 mmol/L) and hypokalemia (2.4 to 3.1 mmol/L; normal range, 3.5 to 5.3 mmol/L). Results of screening for other metabolic or endocrine abnormalities were unremarkable, and there was no familial predisposition. Further studies were consistent with Bartter’s syndrome in showing renal leakage of magnesium and potassium, hyperreninism, and normal serum aldosterone levels.56 Her recurrent pseudogout, hypokalemia, and hypomagnesemia all resolved with indomethacin, 75 mg daily, and oral magnesium supplements.

190 JONES ET AL

Case 2. A 47-year-old woman developed acute intermittent right knee swelling during her first pregnancy (at age 22). She developed similar acute attacks in her left shoulder at age 37 and at the age of 43 was referred after a further episode of acute right knee synovitis, with identification of CPPD crystals in synovial fluid. Many of these episodes were triggered by intercurrent infections or surgery. Serial radiographs over 4 years showed florid, progressive polyarticular CC (Fig 1). She had persistent hypomagnesemia (0.46 to 0.55 mmol/L) but otherwise normal results of screening investi- gations for endocrine and metabolic disease. Studies of renal function showed an isolated, persistent renal wasting of magnesium. We investigated both of her parents, one of three brothers, and both sisters. None have arthropathy, episodes of pseudogout, or radiographic CC, but one sister has borderline hypomagnesemia.

Two controlled studies of biochemical abnormalities have failed to show differences in serum magnesium in patients with CC com-

Fig 1: Anteroposterior radiograph of the left

hip of a 47-year-old patient with hypomagnesemia (case 2) showing chondrocalcinosis of the acetabular labrum and articular cartilage.

pared with controls.‘5*66 A single case report has shown reduced magnesium concentration in the synovial fluid but not serum of a patient with CC6’ the significance of which is unclear.

Hypophosphatasia

Alkaline phosphatase is a major human pyrophosphatase.68,69 Deficiency (hypophosphatasia) results in four rare clinical syndromes that vary according to age of presentation and severity.‘O Although the clinical features of nonlethal forms are dominated by osteomalacia, abnormal dentition, and calcific periarthritis, there are several reports of an association with CC and pseudogout.71-7R The young age of patients in some reported cases (youngest, 23 years) makes a true association likely. In addition, CC may also be a feature of the heterozygous state.79

Hypophosphatasia is a rare cause of sporadic CC.h6 Reductions in synovial fluid alkaline phosphatase concentration have been recorded in some patients with apparently sporadic CC or PA.h8.80-85 However, others have failed to confirm this finding.86-89

Hemochromatosis

CC and a typical arthropathy occur in more than 50% of patients with hemochromatosis90-94 and may be a presenting feature of the disease.95,96 Acute episodes suggestive of crystal synovitis are also described.2”~91~9”~97 Although radiographically there are similarities with PA, some consider the arthropathy of hemochromatosis a distinct entity23,94s98 with characteristic predominance of cystic change, cartilage attri- tion, and, at the hip, osteonecrosis. Similar features have been described in association with other causes of systemic iron overload’? or synovial hemosiderosis. 99,100 However, RA, also associated with synovial hemosiderosis, is nega- tively associated with both CC and CPPD crystal formation.42,48 Factors other than local iron deposition may thus be relevant.4x Once CC or arthropathy is established, treatment of iron overload by venesection does not prevent progression.9X,1D1

Although hemochromatosis is a disease of the sixth decade, there is good evidence that the association with CC is not spurious. When patients with hemochromatosis and CC were


compared with those with sporadic CC, a younger mean age and a marked male preponderance was noted.23 Similarly, a study comparing patients with known cases of hemochromatosis, patients with hyperparathyroidism, and rheumatology outpatient controls (without overt arthropathy) found a similar overall prevalence of CC in the three groups but a younger age of onset in those with hemochromatosis.41 These data must be treated with caution because not all patients with hemochromatosis were studied by radiography, and the control population was highly selected. Overall, however, there is strong evidence that hemochromatosis is associated with premature CC.

With one exception,15 most surveys have failed to show an increased prevalence of hemochromatosis among patients with sporadic CC,U,37,66JM suggesting that hemochromatosis is an unusual cause of sporadic CC. However, a few studies have found elevated levels of immunoreac- tivelo3J04 and bioactivelo5 parathyroid hormone (PTH) in hemochromatosis. The relevance of these findings to idiopathic and hemochromatotic CC remains unclear.

Case 3. A 60-year-old man with long-stand- ing emphysema presented with a 3-year history of anorexia, weight loss, and easy bruising. He drank 8 to 10 pints of beer per week, had never suffered from hepatitis, and had no relevant family history. On examination he had slate- gray pigmentation of the skin, and his liver was smooth, nontender, and palpable 8 cm below the costal margin. On examination of his joints he was found to have Heberdens nodes and mild ankle synovitis but clinically normal knees.

Liver function test results were abnormal, with elevated serum levels of alkaline phosphatase (304 IU/L; normal, 100 to 280 IU/L); y-glutamyl transferase (73 IU/L, normal, <50 IU/L); alanine transaminase (64 III/L, normal, < 40 IU/L); and bilirubin (20 pmol/L, normal, < 17 umol/L). The serum albumin level was normal, but the prothrombin time was increased (international normalized ratio, 2.8). In addition, he was diabetic (fasting glucose, 7.8 mmol/L; normal, 3 to 5 mmol/L) and his serum ferritin level was markedly elevated (4,570 pg/L; normal, 19 to 300 kg/L). Liver biopsy confirmed the diagnosis of hemochromatosis.

Radiographs showed CC of both wrists, knees,

and hips and the pubic symphysis but no radiographic structural damage (Figs 2 and 3). More typical radiographs of hemochromatotic arthropathy are shown for comparison (Figs 4 and 5). Synovial fluid aspirated from the left knee confirmed CPPD crystals (compensated polariz- ing light microscopy).

In spite of a good response in many aspects of his disease to regular venesection, one year later he developed worsening knee, ankle, and metacarpophalangeal pain that has required regular analgesia.

Wilson ‘s Disease

Although Wilson’s disease manifests predom- inantly as hepatic, renal, and neurological disease, a number of locomotor problems are described in association with the disease, including possible CC in at least four cases.106-108 However, in one case the appearance was difficult to differentiate from osteochondritis dissecans,lo8 and in no case have CPPD crystals been positively identified. Thus, in spite of young age in the reported cases, the association remains speculative.

Ochronosis

The rheumatological manifestations of ochronosis are well described.109-111 In peripheral joints a marked loss of both fibrous and hyaline cartilage is seen, making identification of CC

Fig 2: Anteroposterior radiograph of the left knee of a 60-year-old patient with hemochroma-

tosis demonstrating meniscal chondrocalcinosis.

192 JONES ET AL

include 84 patients with hyperuricemia, only 1 additional case of CC was noted.“” Analysis of these results cannot determine whether CC is associated with hyperuricemia per se or only with those patients who form crystals, ie, patients with gout. The latter association may be attributable to promotion of the formation of one type of crystal by another (epitaxy), common factors that promote general crystal formation, or an indirect result of gout-associated joint damage.

Hyperparathyroidism

Although hyperparathyroidism is strongly associated with both CC120,121 and pseudogout,” much of the evidence results from case series. Few studies have addressed the incidence of hyperparathyriodism, pseudogout, and CC in a controlled fashion.

Fig 3: Lateral radiograph of the left knee of the

patient in Fig 2 showing chondrocalcinosis in the

articular cartilages of the femur, tibia, and fibula.

difficult. Although ochronotic patients with both CC”*,“” and synovial CPPD crystals111J1-7-116 have been described, it is unclear whether the patients are particularly young or the CC florid. Evidence for a true association remains weak.

Gout and Hyperuricemia

Initial case series of CC suggested possible associations with gout1J1J4,20 and hyperuricemia.3J1J4 Similarly, series of patients with gout suggested a high incidence of CC.“’ However, most studies attempting to examine this relationship in a controlled fashion have been con- founded by lack of size,15,37,66 poor controls,15,66J02J18 and the coingestion of drugs affecting urate metabolism.15~66J02

One study has properly addressed this issue. Comparing patients with hyperuricemia and episodic acute arthritis with age-matched controls, a significant but small difference in knee CC frequency was observed (4/138 compared with O/142).32 In an extension of the study to

Fig 4: Typical hand radiograph in hemochroma-

tosis with cyst formation in the carpus and prominent involvement at all four metacarpopha-

langeal joints. This 5byear-old man presented with symptomatic knee, hip, and hand arthropathy.

DISEASES ASSOCIATED WITH CPPD CRYSTALS

Fig 5: Hip radiograph of the same patient as Fig

4, showing cyst formation.

Two studies comparing patients with CC and OA controls failed to show an increased prevalence of hyperparathyroidism in the former.15s102 Similarly, a retrospective comparison of patients with hyperparathyroidism and rheumatology outpatient controls showed no difference CC prevalence.41 The rheumatology controls were selected for absence of overt arthropathy, and this preselection and the retrospective nature of some of the data hampers accurate conclusions.

In contrast, an increased prevalence and decreased age of onset of CC was shown in a study comparing 41 hyperparathyroid patients with 100 acute geriatric admissions.27 Similar findings were observed in a prospective, case- control study. 3o Additionally, an increased incidence of pseudogout was observed in the hyperparathyroid group.

Our own experience with 19 patients (13 female, 6 male; median age, 70 years; range, 26 to 90 years) with primary hyperparathyroidism surveyed for CC is summarized in Table 2. The age-adjusted odds ratio for CC in this group compared with a control population is 3.31, and although statistical evaluation of this is pre- cluded by the small numbers involved, the result is clearly in line with other previous studies.

193

CC in hyperparathyroidism is age related,27,30J22 and duration of exposure to elevated PTH levels may be important.122 However, parathyroidectomy does not cause regression of CC or symptomatic improvement.27J23J24 Whether hyperparathyroidism increases the lifetime risk for CC or merely initiates its premature develop- ment in predisposed individuals is unclear.

Pseudogout123J25-127 has also been associated with hyperparathyroidism and parathyroid surgery. The possible mechanism underlying this association is discussed below.

A possible role for PTH in sporadic CC is suggested by several studies showing elevated PTH levels in normocalcemic CC patientsio5, 128-130; negative findings are also reported.15J8s66

Familial Hypocalciutic Hypercalcemia

Familial hypocalciuric hypercalcemia (FHH) is a benign condition characterized by inappropriately low levels of urinary calcium excretion in the face of elevated serum calcium lev- e1s.131-133 Serum parathyroid hormone levels are inappropriately normal or occasionally increased.132,134J35 The first report suggesting a link with CC was of a 54-year-old relative of a proband with neonatal primary hyperparathyroidism.134 An incidence of CC in 5 of 14 related patients aged 47 years or older has also been reported. 132 Although comprehensive evaluation was not performed and precise ages were not given, this is an extremely high prevalence. Further study is needed to confirm an association.

In the Nottingham surveys, 92 patients older than 65 years had suitable knee radiographs and serum calcium measurements. Only 1 patient with hypercalcemia was found, and this patient, an 84-year-old woman, had no evidence of CC.

Table 2: Presence of Chondrocalcinosis of the

Knee and Other Sites in 19 Patients With

Primary Hyperparathyroidism

Age Knee Other Sites

WI CC NoCC CC No CC

<54 0 1 0 1

55-64 2 3 2 3

65-74 3 5 4 4

>75 3 2 2 3

Abbreviation: CC, chondrocalcinosis.

194

Hypercalcemia is an uncommon cause of sporadic CC.

X-Linked Hypophosphatemic Rickets

A single case report has described CC, apparent pseudogout, and chronic arthropathy in a 40-year-old woman with X-linked hypophosphatemic rickets (XLH).136 Although the patient is young, the validity of this association is questionable. The patient described had re- ceived long-term vitamin D therapy, which has previously been anecdotally described as caus- ing CC.“’ A previous series of 38 patients with XLH found CC in 3.138 However, the ages of the patients were not given, and it is difficult therefore to evaluate the extent of any association. Our own experience includes 9 patients with XLH (age range, 21 to 73 years), only 1 of whom had CC, a woman aged 73 years.

Diabetes Mellitus

An increased incidence of diabetes mellitus among patients with CC has been suggested,1,20J23 although several studies have confirmed that this association was spurious, reflect- ing concurrence of two common age-related conditions.13y

In a comparison of 52 diabetic patients and 45 controls, no significant difference in the prevalence of CC was observed.25 In three studies investigating patients with or without CC for diabetes, similar negative results were reported.15J02J40 Surveys of patients selected at random and thoroughly examined for CC and diabetes mellitus have also failed to show any disease association.21s37 In all studies, no distinc- tion between insulin-dependent and non-insulin-dependent patients has been made.

Hypothyroidism

Although hypothyroidism has been previously suggested as a risk factor for CC,14’ a true association is still uncertain. A nonsignificant increase in the prevalence of hypothyroidism was found in a group of 105 patients with PA (101 had CC) compared with 48 patients with OA and no CC.‘02 A low incidence of hypothyroidism was also reported in 105 acute medical admissions, but screening was not complete, and therefore comparisons are invalid. Compar- ing CC patients with spouses again showed no

JONES ET AL

difference in thyroid status.66 However, the validity of the control group in this study is questionable.

Three studies have now investigated the association properly.37,44J42 The first, a survey of 127 hospitalized patients older than 55 years, showed no association between CC and hypothyroidism.37 The second, a comparison of 49 hypothyroid patients and 31 age- and sex-matched controls, showed similar low prevalences of knee CC in both groups .44 The third, a comparison of the rate of CC in 100 hypothyroid patients and 103 age- and sex-matched controls, showed no statistically significant difference between the groups. ‘42 However, all three studies showed a positive trend toward an association.

Our experience with 50 consecutively diag- nosed cases of hypothyroidism is summarized in Table 3. Compared with a control population, the age-stratified odds ratio for CC in hypothyroid patients is 1.83 (95% CI, 0.52 to 6.39). The control population was not systematically screened for metabolic abnormality, and the true odds ratio may be higher.

Alternatively, during a survey of 99 patients older than 65 years, 87 had both thyroid function and knee radiographs performed. Twenty- eight had evidence of CC on the knee radiographs, 4 of whom had elevated thyroid- stimulating hormone (TSH) levels. Fifty-nine had no CC, and 6 of these had elevated TSH levels, for an odds ratio of 1.47 (95% CI, 0.03 to 62.0).

All four studies can be criticized for lack of power,‘hJ42J43 but there is a consistent trend toward an association. Therefore, we conducted a meta-analysis. This analysis is partially flawed because our surveys had specific exclusion crite- ria and age matching is not possible from the

Table 3: Chondrocalcinosis in 50 Patients With

Hypothyroidism

be Chondrocalcinosis

(vr) n Total Hands Knees Hips Symphysis

<54 21 1 (5%) 1

55-64 11 1(9%) 1 1 1

65-74 9 3 (33%) 2 2 1 3

>75 9 3 (33%) 2 3 1 2

NOTE. Total 43 women, 7 men


published data from the Australian survey.37 However, with these caveats, the calculated odds ratio from the four surveys is 1.94 (95% CI, 1.06 to 3.53).

Combining two studies in which there was random testing of an elderly population (ours and that of Gordon et a13’) produces an odds ratio of 1.96 (95% CI, 0.40 to 9.72). A significant but small association between the two conditions seems likely.

Acromegaly

In 1966, a 53-year-old male acromegalic with recurrent attacks of apparent pseudogout of the right knee was reported.lM Crystals were seen in synovial fluid but were not positively identified. Although other case series of acromegalic arthropathy have commented on CC,145-147 the evidence for an association is slight. Five surveys totaling 314 acromegalics comment on only 2 cases of CC,146-150 neither of which is described in sufficient detail to allow comment on age of onset. Conversely, only one case of acromegaly has been noted in case series of CC.15’ There- fore, an association seems unlikely.

MECHANISMS OF PREDISPOSITION

Various mechanisms have been postulated to explain the association between metabolic and endocrine diseases and CC, as summarized in Fig 6. CPPD crystal formation is difficult to study in vivo, and knowledge of parameters affecting it derive from in vitro work.ls2-ls9 Several parameters appear to be important: the “seed” (the calcium and inorganic pyrophosphate (PPi) that are available for combination) and the “soil” (the matrix within which the crystals form as well as tissue factors that promote or inhibit this crystal formation).

The Seed

Elevation of either calcium or PPi concentration could sufficiently increase the ionic product and thus promote CPPD crystal formation and growth. Calcium moves easily into and out of cartilage,15’ and extracellular free calcium concentrations thus influence cartilage concentration. Calcium concentration is tightly controlled by PTH levels, and elevation of calcium concen-

tration in hyperparathyroidism is an obvious mechanism to explain predisposition to CPPD formation in this condition. Once CPPD crystals are formed within cartilage, hypocalcemia would promote their solubilization and hence shedding into the synovial space. This sequence may explain the phenomenon of postparathy- roidectomy pseudogout.

PPi is a by-product of numerous biosynthetic reactions, particularly those using nucleoside triphosphates.161J’j2 PPi concentrations depend not only on rate of synthesis, but also on rate of hydrolyzation by pyrophosphatases, including alkaline phosphatase. 161 Absence of the latter in hypophosphatasia is associated with increased urinary and blood concentrations of PPi,68J63 providing a ready explanation for predisposition to CC in this condition. Relative reductions in synovial fluid alkaline phosphatase levels have been shown in some patients with sporadic CPPD,so-s5 suggesting that localized reductions in pyrophosphatase activity may be relevant in sporadic CPPD crystal formation.

Pyrophosphatases, including alkaline phosphatase, are magnesium dependent. Hypomag- nesemia could thus be expected to promote CPPD formation via inhibition of PPi hydroly- sis, thus resulting in elevated PPi concentrations. In addition, hypomagnesemia may reduce total pyrophosphatase activity.164 Calcium and magnesium metabolism are closely interrelated, and the hypomagnesemia that may occur in hyperparathyroidism provides a further mechanism promoting CPPD formation in this con- text 165,166

Interestingly, FHH is associated with hyper- magnesemia.135 Although at first this appears paradoxical, high concentrations of magne- sium16’ and other divalent cations, including calcium, ferrous iron, and copper,83,84J68J69 inhibit intracellular pyrophosphatases and thus impair CPPD crystal clearance.170

Orthophosphate (P04) has many effects on CPPD formation, including elevation of PPi levels by competitive inhibition of pyrophosphatases,87J67J71 decreased solubility of formed CPPD crystalsg6 and inhibition of CPPD crystal growth.154 It is thus difficult to explain the possible association with XLH.

Elevated synovial fluid PPi levels occur in patients with CPPD crystal deposition.81~86~89J72-177

196 JONES ET AL

-//L-) Inhibition

-_O-+ Stimulation

This PPi is synthesized within the joint,81J73 probably as a by-product of chondrocyte metabolic activity.178-181 Acromegaly,172~182 OA, 82,88,89, 172,173~176~183 and gout89,173 have also been associated with increased synovial fluid or serum PPi levels. This has been suggested as the basis for their association with CC. Because these studies have been performed mostly in arthritic joints, they may be biased by the effect of joint damage on PPi metabolism. Recent work from this unit on synovial fluid from patients and healthy controls, both with asymptomatic, nonarthritic joints, suggests that elevated PPi levels are found in untreated hyperparathyroidism, hemo-

Fig 6: Schematic represen-

tation of pyrophosphate me-

tabolism and CPPD forma-

tion/dissolution showing

the putative effects of meta-

bolic and endocrine factors.

ALP, alkaline phosphatase;

Ca, calcium; Cu, copper; Fe,

iron, GH, growth hormone;

Mg, magnesium; Pi, inor-

ganic phosphate; PPi, inor-

ganic pyrophosphate; PTH,

parathyroid hormone.

chromatosis, and hypomagnesemia.“’ Con- versely, in hypothyroidism low PPi concentrations were measured, suggesting that factors other than increased PPi production are important in the generation of CC. As in previous studies6s elevated urinary PPi levels were only seen in patients with hypophosphatasia.

The Soil

Factors affecting the soil are less well characterized. Crystal formation is promoted by “gels” such as cartilage. The effects of aging,lS4.rS5 0A,186-‘91 trauma,‘57~191 acromegaly,148 ochronosis,llo and heredity49~192~193 on cartilage may ex-


Table 4: Diseases Associated With Chondrocalcinosis

cc Pseudogout Chronic PA

Hypophosphatasia Yes Yes No

Hypomagnesemia Yes Yes No

Hyperparathyroidism Yes Yes No

Hemochromatosis Yes Yes Yes

Hypothyroidism Probably No No

Gout Possibly Possibly No

Acromegaly Possibly No No

FHH Possibly No No

XLH Possibly Possibly Possibly

Wilson’s disease Probably not No No

Ochronosis Probably not No No

Diabetes mellitus No No No

Abbreviations: PA, pyrophosphate arthropathy; FHH, familial hypocalciuric hypercalcemia; XLH, X-linked hypophasphatemic rickets.

plain their associations with both CC and struc- and pseudogout, whereas hemochromatosis, ac- tural arthropathy. Although in hypothyroidism romegaly, and ochronosis also associate with alteration of cartilage matrix seems likely to be chronic arthropathy. This finding suggests that a mechanism promoting CPPD deposition, evi- different mechanisms produce CC/pseudogout dence for this is lacking. and chronic arthropathy.

Divalent and trivalent cations alter the physi- cal properties of the cartilage matrix.194 In addition, iron may be toxic to chondrocytes,ig5 promote formation of oxygen radicals,196 and produce changes in the physicochemical properties of the cartilage matrix.99J94 This may explain why iron deposition results in both CC and pseudogout as well as a specific chondropathy. Copper has properties similar to those iron and perhaps similar effects on cartilage metabolism. In vitro, CPPD crystal formation is inhibited and solubilization of CPPD crystals promoted by magnesium.86J52J53J@J197 Other divalent cations (ferrous iron, copper) could act as nucleat- ing agents although only ferric iron has been shown to do this.19* Urate may act as a nucleat- ing agent, but it is also possible that there may be factors that promote general crystal deposi- tion2092; this is one possible reason for the negative association of FM with both gout*99 and CC.42,48

It seems reasonable to consider a metabolic, endocrine, or familial predisposition if CC is polyarticular or florid. Because CC is relatively rare in patients younger than 55 years, it seems reasonable to screen for hypomagnesemia, hypophosphatasia, and hyperparathyroidism. In men younger than 55 years, particularly if associated with structural arthropathy, hemochromatosis should be excluded. In view of the poor evidence for an association with acromegaly, Wilson’s disease, and ochronosis these should not be investigated unless other clinical or radiographic features suggest these diagnoses.

CONCLUSIONS

After the age of 55, hyperparathyroidism should be considered in all patients with CC because both conditions are more common in this age group. While measuring serum calcium, phosphate, and albumin levels, it seems reasonable to also measure serum alkaline phosphatase levels, even though hypophosphatasia is rare. Screening for hypothyroidism and diabetes mellitus should not be undertaken solely on the basis of the detection of CC.

The diseases associated with CC are summarized in Table 4, and the putative mechanisms responsible are shown in Fig 6. Hyperparathy- roidism, hypomagnesemia, hypophosphatasia, and hypothyroidism seem to associate with CC

ACKNOWLEDGMENT

The authors thank all the Nottingham physicians who

allowed them to examine patients under their care, in

particular Dr David Hosking.

198 JONES ET AL

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Diseases associated with calcium pyrophosphate deposition disease

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